Summary: the stress of oxygen starvation that occurs with sleep disordered breathing (sleep apnea and hypopnea) contributes to metabolic syndrome and high blood pressure. CPAP (continuous positive airway pressure) can help .

I have been finding that people coming to our practice who have been struggling with the depredations of metabolic syndrome including overweight, hypertension, elevated lipids and HgbA1c, etc. have not been evaluated for sleep disordered breathing. A study recently published in The New England Journal of Medicine offers evidence that treatment for sleep apnea can provide significant benefit. The authors state:

“Obstructive sleep apnea is associated with an increased prevalence of the metabolic syndrome and its components…In our double-blind, placebo-controlled trial, we randomly assigned patients with obstructive sleep apnea syndrome to undergo 3 months of therapeutic CPAP followed by 3 months of sham CPAP, or vice versa, with a washout period of 1 month in between.”

They measured anthropometric variables, blood pressure, fasting blood glucose levels, insulin resistance, fasting blood lipids, glycated hemoglobin, carotid intima–media thickness, and visceral fat before and after the real and sham CPAP interventions. Their data showed a worthwhile effect:

“A total of 86 patients completed the study, 75 (87%) of whom had the metabolic syndrome. CPAP treatment (vs. sham CPAP) was associated with significant mean decreases in systolic blood pressure (3.9 mm Hg), serum total cholesterol (13.3 mg per deciliter), non–high-density lipoprotein cholesterol (13.3 mg per deciliter), low-density lipoprotein cholesterol (9.6 mg per deciliter), triglycerides (18.7 mg per deciliter), and glycated hemoglobin (0.2%). The frequency of the metabolic syndrome was reduced after CPAP therapy (reversal found in 11 of 86 patients [13%] undergoing CPAP therapy vs. 1 of 86 [1%] undergoing sham CPAP).”

Clinicians should not fail to consider the possibility of sleep disordered breathing when managing hypertension, overweight and other components of metabolic syndrome. Do you snore or wake in the morning unrefreshed and fall asleep inappropriately during the day? If so, a screening may be appropriate. The authors conclude:

“In patients with moderate-to-severe obstructive sleep apnea syndrome, 3 months of CPAP therapy lowers blood pressure and partially reverses metabolic abnormalities.”

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Summary: In a double-blind crossover study 140 mg per day of resveratrol improved a cluster of markers for metabolism and inflammation that corresponded to the known benefits of caloric restriction.

A study published recently in the journal Cell Metabolism adds more evidence for the beneficial metabolic effects of resveratrol. The authors state:

“Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity.”

They gave 150 mg/day of resveratrol alternating with placebo to eleven obese men in a randomized double-blind crossover study for 30 days. This is quite a small dose (in practice 500 mg two times per day is common). Nonetheless, the benefits were robust:

“Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased.”

In other words, there were meaningful improvements in cellular energy metabolism, liver and blood fats, blood sugar, inflammation, blood pressure and insulin sensitivity (HOMA index). These benefits are similar to those gained from restricting calories. The authors conclude:

“…we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.”

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Summary: Brazil nuts protect against vascular disease in overweight female adolescents.

Recent research published in the journal Nutrition & Metabolism offers evidence that Brazil nuts, besides being more effective at raising serum selenium levels than selenium taken as a supplement, improve the lipid profile and protect against blood vessel damage. The authors state:

“Obesity is a chronic disease associated to an inflammatory process resulting in oxidative stress that leads to morpho-functional microvascular damage that could be improved by some dietary interventions. In this study, the intake of Brazil nuts (Bertholletia excelsa), composed of bioactive substances like selenium, α- e γ- tocopherol, folate and polyunsaturated fatty acids, have been investigated on antioxidant capacity, lipid and metabolic profiles and nutritive skin microcirculation in obese adolescents.”

Their study subjects comprising obese female adolescents were randomized to a group that consumed 15-25 g/day of Brazil nuts in capsules for 16 weeks and a placebo group. Anthropometry, metabolic-lipid profiles, oxidative stress, capillary diameters, functional capillary density, red blood cell velocity (RBCV) were measured at baseline (T0) and after the Brazil nut intervention (T1). What did the data show?

“At T1, BNG [the Brazil nut group] had increased selenium levels, RBCV and RBCVmax and reduced total (TC) and LDL-cholesterol. Compared to PG [placebo group], Brazil nuts intake reduced TC, triglycerides and LDL-ox and increased RBCV.”

In other words, compared to the placebo group, the Brazil nut cohort had better blood vessel function, lower total and LDL cholesterol and, importantly, reduced oxidized cholesterol (LDL-ox, the truly ‘bad’ cholesterol). Naturally, they also had higher selenium levels. The authors conclude:

“Brazil nuts intake improved the lipid profile and microvascular function in obese adolescents, possibly due to its high level of unsaturated fatty acids and bioactive substances.

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Summary: chronic low-grade inflammation is both a damaging result of and a fundamental cause promoting obesity. Management of both weight loss programs and the medical complications of obesity should address the inflammatory component.

An important paper was recently published in the Journal of Clinical Investigation that discusses the role of inflammation in obesity, obesity-related disorders, and metabolic dysfunction. The chronic inflammatory response associated with obesity is has been termed metainflammation:

“Over the past decade, the search for a potential unifying mechanism behind the pathogenesis of obesity-associated diseases has revealed a close relationship between nutrient excess and derangements in the cellular and molecular mediators of immunity and inflammation. This has given birth to the concept of “metainflammation” to describe the chronic low-grade inflammatory response to obesity.”

The authors describe characteristics of the metainflammation of obesity:

“The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time. Childhood obesity may place individuals at risk for lifelong metainflammation, since inflammatory markers are elevated in obese children as young as 3 years old. Superimposed on this chronic inflammation are recurrent acute episodes of nutrition-related immune activation induced by nutrient availability (fasting or high-fat meals)…Non-biased assessments of gene expression networks in adipose tissue identify a robust pattern of overexpressed inflammatory genes associated with obesity and metabolic disease and enriched for macrophage genes…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Importantly, inflammation itself induces insulin resistance that further promotes obesity:

“Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines, decreases in protective factors (e.g., adiponectin), and communication between inflammatory and metabolic cells. For example, direct and paracrine signals from M1 classically activated macrophages can impair insulin signaling and adipogenesis in adipocytes…Similar effects on adipocyte inflammation and glucose transport are generated by signals from activated conventional T cells such as IFN-γ. In parallel, dysregulated macrophage-myocyte and macrophage-hepatocyte signaling can influence insulin sensitivity.”

They discuss the fascinating observation that obesity is associated with an imbalance of immune regulation characterized by the dominance of Th1 (cell-mediated, with a classical proinflammatory macrophage activation state = M1) over Th2 (antibod-mediated, M2) immune inflammatory activity:

“While ATMs [adipose tissue macrophages] likely assume a number of states along the M1/M2 spectrum depending on fat depot location and nutritional status, increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate.”

Most importantly there are a number points where we may intervene to ‘perturb the system’ in the direction of more balanced immune function, thus reducing inflammation and supporting weight loss:

“…maintaining metabolic homeostasis requires a balanced immune response and an integrated network of multiple cell types. Adipose tissue also contains potent tolerogenic CD4+ Tregs that are downregulated by obesity, a potential initiating event in metainflammation. Likewise, there appear to be innate systems by which nutrient signals are utilized to self-limit inflammation. For example, the obesity-induced increase in expression of GPR120, an omega-3 fatty acid (FA) receptor on macrophages capable of attenuating M1 macrophage activation and increasing M2 gene expression, limits inflammation…”

Also of great interest is the role of brain inflammation in promoting obesity:

“The effects of brain inflammation on the metabolic function of peripheral tissues are broad. Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension. Many of these effects are generated by signals from the sympathetic nervous system, which is also capable of inducing inflammatory changes in adipose tissue in response to neuronal injury…The dynamic interplay between hypothalamic inflammation and obesity suggest additional targets for antiinflammatory therapies in obesity. A key extension of these observations is the potential that antiinflammatory pathways may counteract these CNS inflammatory events and improve leptin sensitivity.”

Obesity must be understood as an active agent, both as cause and result, in the web of chronic inflammation. The greatest clinical success in managing weight loss and chronic inflammatory disorders comes from determining and treating the pro-inflammatory factors involved according to each individual case.

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Summary: When designing a dietary strategy for weight loss and maintenance the individual patient’s functional and genetic constitution must be carefully considered, but there is an accumulation of evidence indicating that a high protein, low carbohydrate regimen is a good starting point.

There is a large body of evidence that can instruct us in how to fashion an eating plan to promote both short and long-term success in weight loss and healthy body composition. As a paper published in the journal Obesity demonstrates, the way many Americans eat—referred to as a ‘cafeteria diet’ (CF)—is worse than a diet high in lard. The authors note:

“Obesity has reached epidemic proportions worldwide and reports estimate that American children consume up to 25% of calories from snacks. Several animal models of obesity exist, but studies are lacking that compare high-fat diets (HFD) traditionally used in rodent models of diet-induced obesity (DIO) to diets consisting of food regularly consumed by humans, including high-salt, high-fat, low-fiber, energy dense foods such as cookies, chips, and processed meats.”

They investigated the effects on weight gain and inflammation of a cafeteria diet (CAF) compared to a lard-based 45% HFD by feeding their rodent models either HFD, CAF or a chow control for 15 weeks. Their data clearly show that even consuming almost half the diet in lard is better than the lethal mix that many now consume:

“Body weight increased dramatically and remained significantly elevated in CAF-fed rats compared to all other diets. Glucose- and insulin-tolerance tests revealed that hyperinsulinemia, hyperglycemia, and glucose intolerance were exaggerated in the CAF-fed rats compared to controls and HFD-fed rats.”

Moreover, the cafeteria diet was markedly worse in promoting inflammation:

“It is well-established that macrophages infiltrate metabolic tissues at the onset of weight gain and directly contribute to inflammation, insulin resistance, and obesity. Although both high fat diets resulted in increased adiposity and hepatosteatosis, CAF-fed rats displayed remarkable inflammation in white fat, brown fat and liver compared to HFD and controls. In sum, the CAF provided a robust model of human metabolic syndrome compared to traditional lard-based HFD, creating a phenotype of exaggerated obesity with glucose intolerance and inflammation.”

A study published in The New England Journal of Medicine examined specific dietary factors that stand out in their contribution to obesity noting that they…

“…may affect the success of the straightforward-sounding strategy “eat less and exercise more” for preventing long-term weight gain.”

They performed investigations involving 120,877 U.S. women and men who were free of chronic diseases and not obese at baseline for as long as twenty years. Relationships between changes in lifestyle factors and weight change were evaluated every four years. There were several factors that stood out:

“Within each 4-year period, participants gained an average of 3.35 lb. On the basis of increased daily servings of individual dietary components, 4-year weight change was most strongly associated with the intake of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unprocessed red meats (0.95 lb), and processed meats (0.93 lb) and was inversely associated with the intake of vegetables (−0.22 lb), whole grains (−0.37 lb), fruits (−0.49 lb), nuts (−0.57 lb), and yogurt (−0.82 lb)…Other lifestyle factors were also independently associated with weight change, including physical activity (−1.76 lb across quintiles); alcohol use (0.41 lb per drink per day), smoking (new quitters, 5.17 lb; former smokers, 0.14 lb), sleep (more weight gain with <6 or >8 hours of sleep), and television watching (0.31 lb per hour per day).”

Potatoes are clearly ‘sugar grenades’, but in my opinion further studies are required to examine the difference between red meat from animals treated with hormones and fed a grain diet versus those that are free of growth-stimulating medications and eat mainly grass.

With the most egregious insults to a metabolically healthy diet out of the way, we can proceed to the roles of glycemic index and glycemic load on weight loss as examined in a study published recently in the Journal of Nutrition:

“This study assessed the effect of changes in glycemic index (GI) and load (GL) on weight loss and glycated hemoglobin (HbA1c) among individuals with type 2 diabetes beginning a vegan diet or diet following the 2003 American Diabetes Association (ADA) recommendations.”

99 subjects with type 2 diabetes were randomized to follow 1 of 2 diet treatments for 22 weeks. Glycemic index and glycemic load changes were assessed and their relationships with changes in weight and HbA1C were calculated. (Glycemic index is a metric for rate which a food will cause blood sugar to rise. Glycemic load is determined by multiplying the glycemic index by the amount of carbohydrate in grams provided by a food and dividing the total by 100; this amounts to the sum of the glycemic loads for all foods consumed in the diet.) Interestingly, glycemic index predicted weight gain while glycemic load did not:

“…the vegan group reduced GI to a greater extent than the ADA group, but GL was reduced further in the ADA than the vegan group. GI predicted changes in weight, adjusting for changes in fiber, carbohydrate, fat, alcohol, energy intake, steps per day, group, and demographics, such that for every point decrease in GI, participants lost ~0.2 kg (0.44 lb)…Weight loss was a predictor of changes in HbA1C. GL was not related to weight loss or changes in HbA1C.”

Thus glycemic index takes precedence over glycemic load in choosing foods for weight loss and blood sugar regulation. Also notable was the finding regarding GI and HbA1C:

“GI was not a predictor for changes in HbA1C after controlling for weight loss.”

Every wonder why a patient’s HbA1C didn’t go down even though they were eating a low GI diet? This shows that if they don’t lose weight as a result, the the HbA1C will tend to stay the same. The authors conclude:

“A low-GI diet appears to be one of the determinants of success of a vegan or ADA diet in reducing body weight among people with type 2 diabetes. The reduction of body weight, in turn, was predictive of decreasing HbA1C.”

The interesting difference between the effects of glycemic index and glycemic load revealed here help to explain the inconsistency noted in a review published earlier in journal IUBMB (International Union of Biochemistry and Molecular Biology) Life:

“Recently, due to its possible link to appetite control and metabolism, several clinical studies have assessed the effect of low glycemic index (GI) and glycemic load (GL) diets on weight loss. To determine the application of GI/GL in the prevention and treatment of obesity, we searched several databases and identified 23 clinical trials that examined low GI/GL diets and weight loss as the primary outcome measure.”

Here the pooling of GI and GL seems to have obfuscated the issue. The authors conclude:

“Over the past decade, the body of research that links low GI/GL diets to weight loss has grown rapidly and significantly. While there is a significant amount of inconsistency in the current findings, the majority of studies found a trend that favored low GI/GL diets in weight loss.”

Moreover…

“…the benefits of low GI and GL diets extend beyond weight loss and have favorable effects on obesity-related risk factors such as heart disease and diabetes by mechanisms that are independent of weight loss.”

What about protein versus carbohydrate for weight loss? A number of investigators have examined this question, but an interesting study published recently in the Nutrition Journal corrects some important limitations in earlier work:

“Studies have suggested that moderately high protein diets may be more appropriate than conventional low-fat high carbohydrate diets for individuals at risk of developing the metabolic syndrome and type 2 diabetes. However in most such studies sources of dietary carbohydrate may not have been appropriate and protein intakes may have been excessively high. Thus, in a proof-of-concept study we compared two relatively low-fat weight loss diets – one high in protein and the other high in fiber-rich, minimally processed cereals and legumes – to determine whether a relatively high protein diet has the potential to confer greater benefits.”

They eighty-three overweight or obese women to either a moderately high protein (30% protein, 40% carbohydrate) diet (HP) or to a high fiber, relatively high carbohydrate (50% carbohydrate, > 35 g total dietary fiber, 20% protein) diet (HFib) for 8 weeks. During that time their energy intakes were reduced by 478 to 955 calories per day to achieve weight loss of between 0.5 and 1 kg per week. Which diet resulted in better weight loss?

“Participants on both diets lost weight (HP: -4.5 kg and HFib: -3.3 kg), and reduced total body fat (HP: -4.0 kg and HFib: -2.5 kg, and waist circumference (HP: -5.4 cm and HFib: -4.7 cm), as well as total and LDL cholesterol, triglycerides, fasting plasma glucose and blood pressure. However participants on HP lost more body weight (-1.3 kg) and total body fat (-1.3 kg). Diastolic blood pressure decreased more on HP (-3.7 mm Hg).”

High protein wins out over high carbohydrate, even when the carbohydrate is high fiber. The authors conclude:

“A realistic high protein weight-reducing diet was associated with greater fat loss and lower blood pressure when compared with a high carbohydrate, high fiber diet in high risk overweight and obese women.”

Importantly, the benefits of a high protein to carbohydrate ratio diet include the slowing of tumor growth and prevention of cancer initiation as described in an excellent paper (you may wish to read it in its entirety) published recently in the journal Cancer Research. It includes a significant consideration for reducing carbohydrate by increasing protein rather than fat. The authors state:

“Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction–induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein.”

They were able to formulate diets that demonstrated that the tumor inhibiting effects were due to factors other than weight loss from calorie restriction (CR):

“To exploit the fact that cancer cells rely more heavily on glycolysis than normal cells, we designed low CHO, high protein diets to see if we could limit BG and tumor growth. In designing our diets, we wanted to avoid NCKDs [no calorie ketogenic diets] because of the difficulty in achieving long-term compliance with no CHO diets in potential future human studies and because Masko and colleagues recently reported that a 10% or 20% CHO diet slows tumor growth as effectively as NCKDs. Following early studies with 8% CHO diets, using 10% and 15% CHO, high protein diets in which 70% of the CHO was in the form of amylose, we found that, compared with a Western diet, they were indeed capable of reducing BG, insulin, and lactate levels and, importantly, in slowing the growth of implanted murine and human tumors, with little or no effects on mouse weight.”

There is good reason to apply these finding to human case management:

“Consistent with the notion that reducing BG in humans can be beneficial, there is a wealth of epidemiologic evidence showing a clear association between BG and/or insulin levels (which are determined by BG levels) and the incidence of human cancers. Thus, although our studies were conducted, out of necessity, with mice, the fact that human BG can be significantly reduced with low CHO diets and the association of many cancers with high BG levels suggest that our findings are very likely relevant to human cancers as well, particularly in cancers that have been associated with higher baseline BG and/or insulin levels, such as pancreatic, breast, colorectal, endometrial, and esophageal cancers.”

This also has application to prostate cancers:

“In addition to these cancers, a low CHO diet may also be beneficial in early-stage prostate cancer, even though it is not typically detectable by PET. This is because the metastases of these tumors kill the patients and, given the pivotal role of lactate in promoting metastasis, our low CHO diets could significantly reduce metastasis by reducing tumor-associated lactate levels.”

Regarding concerns about the impact on kidney function…

“In terms of macronutrient composition, even though high protein has been shown to promote satiety—thus reducing obesity, BG, and insulin levels—and enhance both antitumor immunity, through amino acid supplementation, and life span, we were concerned, based on the literature, that high protein levels might cause kidney damage. More recent data, however, suggest that this may only occur in individuals with existing chronic kidney disease and that in normal people, the increase in glomerular filtration rate and kidney cellularity that occur with long-term high protein consumption may be a normal response.”

Incidentally, amylose starch prevents DNA damage in the colon that may otherwise be caused by red meat:

“Interestingly, colonic cancer-inducing damage caused by red meats may be avoided with high amylose, low CHO diets. These studies suggest that macronutrient sources and combinations are very important…”

The authors conclude:

“Our study, herein, shows that a high amylose containing low CHO, high protein diet reduces BG, insulin, and glycolysis, slows tumor growth, reduces tumor incidence, and works additively with existing therapies without weight loss or kidney failure. Such a diet, therefore, has the potential of being both a novel cancer prophylactic and treatment, warranting further investigation of its applicability in the clinic, especially in combination with existing therapies.”

Regarding weight loss, what if exercise is added to the program? Will high protein still beat high carbohydrate. A study published in the journal The Physician and Sports Medicine studies this question as the authors set out to…

“…determine whether sedentary obese women with elevated levels of homeostatic model assessment (HOMA) insulin resistance (ie, > 3.5) experience greater benefits from an exercise + higher-carbohydrate (HC) or carbohydrate-restricted weight loss program than women with lower HOMA levels.”

221 women who participated in a 10-week supervised exercise and weight loss program were assigned low-fat (30%) diets that consisted of 1200 kcals per day for 1 week (phase 1) and 1600 kcals per day for 9 weeks (phase 2) with either high carbohydrate (HC) or higher protein (HP). Fasting blood samples, body composition, anthropometry, resting energy expenditure, and fitness measurements were obtained at the beginning and end. Again we see high protein win out over high carbohydrate:

“Subjects in the HP group experienced greater weight loss (−4.4 ± 3.6 kg vs −2.6 ± 2.9 kg), fat loss (−3.4 ± 2.7 kg vs −1.7 ± 2.0 kg), reductions in serum glucose (3% vs 2%), and decreases in serum leptin levels (−30.8% vs −10.8%) than those in the HC group.”

The authors conclude:

“A carbohydrate-restricted diet promoted more favorable changes in weight loss, fat loss, and markers of health in obese women who initiated an exercise program compared with a diet higher in carbohydrate. Additionally, obese women who initiated training and dieting with higher HOMA levels experienced greater reductions in blood glucose following an HP diet.”

Regarding the use of vegetable or fruit juices in programs designed for weight loss, a study published in the journal Obesity demonstrates that this is counter-productive:

“Beverage consumption has been implicated in weight gain, but questions remain about the veracity of the association, whether the relationship is causal and what property of beverages is responsible. It was hypothesized that food form is the most salient attribute. Thus, a randomized controlled trial of food form was conducted. Energy-matched beverage or solid forms of fruits and vegetables were provided to 34, lean or overweight/obese adults for two 8-week periods with a 3-week washout interspersed.”

During the solid food arm of the study the lean group had no significant weight change while the overweight/obese group had weight gain, but during the juice phase…

“In contrast, incomplete dietary compensation and weight gain occurred in both the lean (43%) and overweight/obese (61%) groups during the beverage arm…These data demonstrate energy consumed as beverages may be especially problematic for weight gain.”

And for the carbohydrates that are consumed, a curious study also published in Obesity offers evidence that eating them mainly at dinner further aids in weight loss, satiety and more:

“This study was designed to investigate the effect of a low-calorie diet with carbohydrates eaten mostly at dinner on anthropometric, hunger/satiety, biochemical, and inflammatory parameters. Hormonal secretions were also evaluated. Seventy-eight police officers (BMI >30) were randomly assigned to experimental (carbohydrates eaten mostly at dinner) or control weight loss diets for 6 months. On day 0, 7, 90, and 180 blood samples and hunger scores were collected every 4 h from 0800 to 2000 hours. Anthropometric measurements were collected throughout the study.”

Amazingly…

“Greater weight loss, abdominal circumference, and body fat mass reductions were observed in the experimental diet in comparison to controls. Hunger scores were lower and greater improvements in fasting glucose, average daily insulin concentrations, and homeostasis model assessment for insulin resistance (HOMAIR), T-cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were observed in comparison to controls. The experimental diet modified daily leptin and adiponectin concentrations compared to those observed at baseline and to a control diet.”

Wow…all that just from shifting carbohydrates to dinner. The authors conclude:

“A simple dietary manipulation of carbohydrate distribution appears to have additional benefits when compared to a conventional weight loss diet in individuals suffering from obesity. It might also be beneficial for individuals suffering from insulin resistance and the metabolic syndrome.”

The scientific data addressing various aspects of dietary fat is treated in a separate post, but it’s suitable here to consider a study published in The Journal of Clinical Endocrinology & Metabolism offering evidence that a low carbohydrate diet is equivalent to a low fat diet for weight loss:

“Overweight and obese men and women (24–61 yr of age) were recruited into a randomized trial to compare the effects of a low-fat (LF) vs. a low-carbohydrate (LC) diet on weight loss…Subjects on the LF diet consumed an average of 17.8% of energy from fat, compared with their habitual intake of 36.4%, and had a resulting energy restriction of 2540 kJ/d [585 calories]. Subjects on the LC diet consumed an average of 15.4% carbohydrate, compared with habitual intakes of about 50% carbohydrate, and had a resulting energy restriction of 3195 kJ/d [763 calories].”

At the end of the study period the LC group lost as much weight and had better insulin regulation:

“Both groups of subjects had significant weight loss over the 10 wk of diet intervention and nearly identical improvements in body weight and fat mass. LF subjects lost an average of 6.8 kg and had a decrease in body mass index of 2.2 kg/m2, compared with a loss of 7.0 kg and decrease in body mass index of 2.1 kg/m2 in the LC subjects. The LF group better preserved lean body mass when compared with the LC group; however, only the LC group had a significant decrease in circulating insulin concentrations.”

The authors conclude:

“”These data suggest that energy restriction achieved by a very LC diet is equally effective as a LF diet strategy for weight loss and decreasing body fat in overweight and obese adults.”

Bottom line: When designing a dietary strategy for weight loss and maintenance the individual patient’s functional and genetic constitution must be carefully considered (inflammation, immune regulation, insulin sensitivity, allergy, intestinal permeability, sleep disordered breathing and hormonal function are fundamentals); but there is an accumulation of evidence suggesting that a high protein, low carbohydrate regimen is a good starting point.

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There is an accumulation of fascinating scientific evidence that intermittent calorie restriction (ICR) offers a number of advantages over continuous calorie restriction (CCR) for successful long term weight loss and the ‘turning on’ of genes that favor longevity. Consider a study published recently in the International Journal of Obesity in which the investigators compared ICR and CCR for weight loss and metabolic disease risk markers in overweight women. The authors state:

“Excess weight and weight gain during adult life increases the risk of several diseases including diabetes, cardiovascular disease (CVD), dementia, certain forms of cancer including breast cancer, and can contribute to premature death. Observational and some randomised trials indicate that modest weight reduction (>5% of body weight) reduces the incidence and progression of many of these diseases. Although weight control is beneficial, the problem of poor compliance in weight loss programmes is well known.”

Moreover…

“Even where reduced weights are maintained, many of the benefits achieved during weight loss, including improvements in insulin sensitivity, may be attenuated due to non-compliance or adaptation. Sustainable and effective energy restriction strategies are thus required.”

In other words, a method that can be comfortable enough to be accepted into daily life for the long that also avoids loss of improvements due to adaption is required.

“One possible approach may be intermittent energy restriction (IER), with short spells of severe restriction between longer periods of habitual energy intake. For some subjects such an approach may be easier to follow than a daily or continuous energy restriction (CER) and may overcome adaption to the weight reduced state by repeated rapid improvements in metabolic control with each spell of energy restriction.”

So the authors set out to…

“…compare the feasibility and effectiveness of IER with CER for weight loss, insulin sensitivity and other metabolic disease risk markers…This is the largest randomised comparison of an isocalorific intermittent vs. continuous energy restriction to date in free living humans..”

They designed a randomised comparison of a 25% energy restriction as IER (~2266 kJ/day which equals 541 calories per day for 2 days/week) or CER (~6276 kJ/day equaling 1499 calories each day for 7 days/week) in 107 overweight or obese premenopausal women for a 6 month study period. They measured an extensive list of biomarkers at baseline and after 1, 3 and 6 months: weight, anthropometry (size, weight and proportions), biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, IGF-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain derived neurotrophic factor. What did the data show?

“Last observation carried forward analysis showed IER and CER are equally effective for weight loss, mean weight change for IER was −6.4 kg vs. −5.6 kg for CER. Both groups experienced comparable reductions in leptin, free androgen index, high sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than CER; difference between groups for fasting insulin −1.2 μU/ml, and insulin resistance −1.2 μU/mmol/L.”

Regarding concerns about tolerance…

“A recent blinded trial of a 2 day VLCD [very low calorie diet] (1311 kJ/day [313 calories per day!]) reported no adverse effects on cognition, energy levels, sleep or mood, suggesting symptoms are expected with VLCD and therefore experienced and could potentially be overcome with appropriate counselling. Importantly IER did not lead to overeating on non-VLCD days.”

The authors briefly summarize the results of their comparison of IER and CER by concluding:

“IER is as effective as CER in regards to weight loss, insulin sensitivity and other health biomarkers and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.”

That’s not all though. The authors additionally note an extremely interesting observation with profound implications and potential for benefit regarding additional benefits of an intermittent very low calorie method:

“Recent reviews speculate that IER may be associated with greater disease prevention than CER due to increased cellular stress resistance, in particular increased resistance to oxidative stress. This is thought to be mediated by ‘hormesis’ whereby the moderate stress of energy restriction increases the production of cytoprotective, restorative proteins, antioxidant enzymes and protein chaperones. Alternate day fasting has been linked to increased SIRT-1 gene expression in muscle, and to greater neuronal resistance to injury compared to CER in C57BL/6 mice. The tendency for greater improvements in oxidative stress markers in our IER than in the CER group may support these assertions. Declines in long term protein oxidation product aggregates suggest IER as a possible activator of catabolism and autophagy.”

In other words, intermittent calorie restriction can be as effective as continuous calorie restriction for weight loss, but have the added advantage of ‘turning on’ genes beneficial for health and longevity and preventing adaptation that would result in regaining weight.

Other investigators also have compared intermittent with continuous calorie (daily) calorie restriction as in a study published recently in the journal Obesity Reviews. The authors set out to…

“…evaluate and compare the effects of daily CR versus intermittent CR on weight loss, fat mass loss, lean mass retention and visceral fat mass reduction, in overweight and obese adults.”

They undertook a review of studies that were randomized control trials, had a primary endpoint of weight loss and/or body composition changes, used daily CR or intermittent CR as the primary focus of the intervention; had a study duration of 4–24 weeks, and involved adult populations who were overweight or obese subjects but not diabetic. These included 11 daily continuous calorie restriction trials and five intermittent CR trials published between 2000 and 2010, along with two unpublished trials of intermittent CR from their own lab. What did all these studies add up to?

“Results reveal similar weight loss and fat mass loss with 3 to 12 weeks’ intermittent CR (4–8%, 11–16%, respectively) and daily CR (5–8%, 10–20%, respectively). In contrast, less fat free mass was lost in response to intermittent CR versus daily CR.”

This is a significant advantage of ICR over CCR (continuous = daily calorie restriction). The authors conclude by stating:

“In sum, intermittent CR and daily CR diets appear to be equally as effective in decreasing body weight, fat mass, and potentially, visceral fat mass. However, intermittent restriction regimens may be superior to daily restriction regimens in that they help conserve lean mass at the expense of fat mass. These findings add to the growing body of evidence showing that intermittent CR may be implemented as another viable option for weight loss in overweight and obese populations.”

Numerous other studies have examined the distinctive benefits of intermittent calorie restriction. A paper published recently in the journal Oncogene investigates the positive effects of brief ICR compared to CCR for cancer patients. The authors state:

“The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting—no calorie intake—induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels.”

They point out that cancer cells are unable to respond to the positive stimuli of calorie restriction:

“Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells.”

Moreover…

“Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks–months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans.”

They go on to review studies on fasting, cellular protection and chemotherapy resistance, and futher compare them to those on continuous calorie restriction and cancer treatment. The authors conclude:

“Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.”

A study published in the Journal of Molecular and Cellular Cardiology offers evidence that intermittent calorie restriction activates genes that help in the recovery from heart damage. The authors state:

“Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI).“

Two weeks after myocardial ischemia was induced in their study animals, they were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks the authors evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival. The results were truly striking:

“Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival). The heart weight body weight ratio was significantly less in the MI-IF group compared to the MI-NF group (3.4 ± 0.17 versus 3.9 ± 0.18. Isolated heart perfusion studies exhibited well preserved cardiac functions in the MI-IF group compared to the MI-NF group. Molecular studies revealed the upregulation of angiogenic factors such asHIF-1-α (3010 ± 350% versus 650 ± 151%), BDNF (523 ± 32% versus 110 ± 12%), and VEGF (450 ± 21% versus 170 ± 30%) in the fasted hearts. Immunohistochemical studies confirmed increased capillary density in the border area of the ischemic myocardium and synthesis VEGF by cardiomyocytes. Moreover fasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone.”

This is a dramatic indication that intermittent calorie restriction can be used to protect and repair heart tissue. The authors conclude:

“Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.”

Another fascinating study published recently in the journal Cancer Prevention Research demonstrates that intermittent calorie restriction is clearly superior to both continuous calorie restriction and an unrestricted diet for breast cancer prevention. Specifically, the authors studied…

“The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels…in relation to mammary tumorigenesis.”

Their subjects were assigned to ad libitum fed, ICR (3-week 50% caloric restriction followed by 3-wks 100% AL consumption), and CCR groups.

“Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad.”

This amounts to an impressive ‘turning on’ of genes that protect against breast cancer for ICR. In conclusion…

“…we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.”

A paper published in the journal Nutrition and Cancer demonstrates that ICR offers a greater protective effect than CCR for prostate cancer. The authors state:

“Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development.”

Their animal models for prostate cancer were assigned to ad libitum (AL), ICR, and CCR groups. There were distinctive differences according to the manner of calorie restriction that dramatically favored the ICR over both the AL and CCR cohorts:

“ICR mice were older at tumor detection than AL and CCR mice. There was no difference for age of tumor detection between AL and CCR mice. Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups.”

Not only did the subjects on CCR live longer with healthier biomarkers than the ones on either the free diet or CCR, there was no difference between the AL and CCR groups for age of tumor detection or survival. The implication is exciting: the benefits were due not to the weight loss component but to the way in which ICR affects gene expression. The authors conclude:

“These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.”

A paper published in the The Journal of Nutritional Biochemistry also offers evidence that intermittent calorie restriction protects heart tissue:

“It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats.”

The authors showed by echocardiographic analysis of heart structur and function that intermittent fasting attenuates the disease related increase in heart thickness, end systolic and diastolic volumes, and ejection fraction. Additionally…

“The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI.”

There is now a large body of evidence showing that ICR increases the protective hormone adiponectin much more than CCR. The authors conclude:

“Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.”

A paper published in the journal Ageing Research Reviews discusses how IFR and CCR can protect the brain from accelerated neurodegeneration associated with aging. The authors note:

“The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span.”

As we’ve seen regarding cardioprotection and tumorigenesis…

“CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease.”

These studies comprise the first post that illustrates the scientific basis for the Lapis Light Weight Loss & Gene Modulation Program that customizes intermittent calorie restriction according to the individual’s weight management and other health needs. Subsequent posts will offer additional scientific evidence important for other aspects of the program.

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More evidence that dairy foods contain agents with antiinflammatory and antioxidant properties is presented in a study published recently in The American Journal of Clinical Nutrition showing reductions in damaging inflammatory biomarkers. The authors state:

“Oxidative and inflammatory stress are elevated in obesity and are further augmented in metabolic syndrome. We showed previously that dairy components suppress the adipocyte- and macrophage-mediated generation of reactive oxygen species and inflammatory cytokines and systemic oxidative and inflammatory biomarkers in obesity…The objective of this study was to determine the early (7 d) and sustained (4 and 12 wk) effects of adequate-dairy (AD) compared with low-dairy (LD) diets in subjects with metabolic syndrome.”

Their forty overweight or obese subjects with metabolic syndrome were randomly assigned to receive either an ‘adequate dairy diet’ (defined as 3.5 daily servings) or ‘low dairy diet’ (less than half a daily serving) form of weight-maintenance diet for 12 weeks. They measured oxidative and inflammatory biomarkers at the start and after 1, 4, and 12 weeks as primary outcomes, along with body weight and composition to start and after 4, and 12 weeks as secondary outcomes. Their data showed a dramatic difference for the ‘adequate dairy’ diet:

“AD decreased malondialdehyde and oxidized LDL at 7 d (35% and 11%, respectively), with further decreases by 12 wk. Inflammatory markers were suppressed with intake of AD, with decreases in tumor necrosis factor-α at 7 d and further reductions through 12 wk (35%); decreases in interleukin-6 (21%) and monocyte chemoattractant protein 1 (14% decrease at 4 wk, 24% decrease at 12 wk); and a corresponding 55% increase in adiponectin at 12 wk. LD exerted no effect on oxidative or inflammatory markers. Diet had no effect on body weight; however, AD significantly reduced waist circumference and trunk fat, and LD exerted no effect.”

While these findings don’t obviate the need to attend to the possibility of dairy allergies or the quality of dairy foods consumed, this is strong evidence that there agents in an ‘adequate dairy’ diet that can do more than a low dairy diet even when the same amount of weight is lost.

“Data from this study show that an increase in dairy intake from suboptimal to adequate levels (≈3.5 servings/d) significantly attenuates both oxidative and inflammatory stress in metabolic syndrome. Notably, although these effects may result, in part, from reductions in adiposity on higher dairy diets, the rapid onset (within the first 7 d of dietary change) suggest that there is an adiposity-independent effect as well. This is further supported by our previous evidence that showed direct effects of dairy components on adipocyte cytokine expression and secretion.”

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New research just published in the journal Obesity contributes to the evidence for weighty metabolic consequences of the hypoxia (reduced oxygen saturation) that occurs with sleep disordered breathing. The authors state:

“The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR [insulin resistance] and NAFLD [non-alcoholic fatty liver disease] in lean mice and mice with diet-induced obesity (DIO).”

They fed the study subjects either a high fat or regular diet for 12 weeks, after which they were exposed to CIH or normal room air as a control condition for 4 weeks. Then they measured fasting blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and performed an intraperitoneal glucose tolerance test. Their data paints an interesting picture:

“In DIO mice, body weight remained stable during CIH and did not differ from control conditions…Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index, whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index, and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice.”

In other words, even though hypoxia did not further increase the body weight of the subjects with diet induced obesity, the metabolic effects including glucose intolerance, inflammation, fatty liver disease and oxidative stress were severe. I often find that the possibility of sleep disordered breathing has been overlooked in the work-up of patients with overweight or metabolic syndrome. This research adds to the compelling evidence that clinicians should bear this in mind.

“In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.”

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As clinicians and most lay readers know, healthy weight loss and weight maintenance require healthy insulin signaling. Insulin receptor resistance due to excessive glycemic stimulation results in higher compensatory insulin levels that force the storage of calories as fat. Inflammation also contributes to insulin resistance, with metabolic syndrome and its associated weight gain and eventual type 2 diabetes. A fascinating study just published in the journal Obesity describes how B cell-activating factor (BAFF) contributes to the development of insulin resistance. BAFF can be induced by food hypersensitivity and allergic reactions. The authors state:

“Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell-activating factor (BAFF) in the induction of insulin resistance.”

They examined BAFF levels in the blood and visceral fat of obese mice, which they found to be increased compared to normal control mice…

“Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate-1 in adipocytes.”

In other words, BAFF not only directly induced insulin resistance, but altered the expression of genes related to insulin receptor function and fat inflammatory cytokine (adipokine) production. The authors concluded:

“We propose that autocrine or paracrine BAFF and BAFF-receptor (BAFF-R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production.”

We can also appreciate an earlier paper published in the journal Experimental & Molecular Medicine that also identifies BAFF as an adipokine that links inflammation with obesity. The authors state:

“In the current study, we verified that BAFF expression is increased during adipocyte differentiation…We sought to identify known BAFF receptors (BAFF-R, BCMA, and TACI) in adipocytes, and determined that all three were present and upregulated during adipocyte differentiation…BAFF-R and BCMA expression levels were upregulated under pro-inflammatory conditions…”

They also demonstrated that the BAFF receptors BAFF-R and BCMA were downregulated by rosigliatazone treatment. (Rosigliatzone, trade name Avandia, is a thiazolidinedione type anti-diabetic drug with anti-inflammatory properties whose use has been complicated by serious side effects.) In other words, inflammation associated with BAFF signaling promoted insulin resistance and obesity. The authors conclude:

“Taken together, our results suggest that BAFF may be a new adipokine, representing a link between obesity and inflammation.”

Incidentally, as the authors of a review just published in the Journal of Clinical Investigation note, obesity-associated inflammation has serious global effects:

“The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity…The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases.”

Moreover…

“The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Clinicians should never overlook the role of the gut-associated immune tissue (GALT) in disorders of chronic inflammation. A paper just published in Current Opinion in Clinical Nutrition & Metabolic Care highlights this in the link between intestinal inflammation, obesity and insulin resistance. The authors state:

“Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity…”

They go on to summarize…

“…the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms.”

Of course, food allergy and hypersensitivity are major causes of intestinal inflammation. Regrettably, many practitioners may wrongly assume that the phenomenon of inflammation triggered by food sensitivity is limited to the classically defined IgE-mediated acute hypersensitivity reaction. In fact, there are a number of pathways by which food sensitivity can elicit an inflammatory response. A very important study just published in Alimentary Pharmacology & Therapeutics makes this clear in regard to BAFF, which we now understand to be linked to obesity and insulin resistance. The authors first note that…

“Medically confirmed hypersensitivity reactions to food are usually IgE-mediated. Non-IgE-mediated reactions are not only seldom recognized but also more difficult to diagnose.”

They set out to…

“…examine B cell-activating factor (BAFF) in serum and gut lavage fluid of patients with self-reported food hypersensitivity, and to study its relationship to atopic disease.”

So they examined the gut lavage fluid obtained from 60 patients with self-reported food hypersensitivity and the serum from 17 others. From 20 healthy control subjects they obtained gut lavage fluid, along with serum from 11 of them. They then measured BAFF in both serum and the gut lavage fluid. Their findings are most interesting:

“B cell-activating factor levels in serum and gut lavage fluid were significantly higher in patients than in controls…There was no significant correlation between serum levels of BAFF and IgE.”

In other words, patients with food hypersensitivity produced significantly higher levels of BAFF–and IgE failed as an indicator of BAFF associated inflammation with food hypersensitivity. The authors add in their conclusion:

“The results suggest that BAFF might be a new mediating mechanism in food hypersensitivity reactions. Significantly higher levels in non-atopic compared with atopic patients, and no correlation between BAFF and IgE, suggest that BAFF might be involved particularly in non-IgE-mediated reactions.”

Unfortunately, food hypersensitivity is too often dismissed by many in the medical community as a poorly understood phenomenon that ends up being ignored in clinical practice. A clinical study review recently published in the Scandinavian Journal of Gastroenterology investigates this issue and observes the role of BAFF:

“Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years’ interdisciplinary research program dealing with such patients.”

The studies included more than 400 adults who were referred to a university hospital because of gastrointestinal complaints that they attributed to food hypersensitivity. Most not only fulfilled criteria for irritable bowel syndrome…

“…In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life.”

Sadly…

“Despite extensive examinations, food allergy was seldom diagnosed…However, psychological factors could explain only approximately 10% of the variance in the patients’ symptom severity and 90% of the variance thus remained unexplained.”

Moreover…

“Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and “IgE-armed” mast cells.”

Atopic dermatitis (the most common form or eczema, also linked to food sensitivity) has been shown to be associated with high levels of B cell-activating factor (BAFF) in a paper published not long ago in the journal Clinical and Experimental Dermatology. In order to investigate the role of BAFF in serum of patients with atopic dermatitis (AD)…

“Levels of serum BAFF, a proliferation-inducing ligand (APRIL) and total serum IgE level, and total eosinophil count were measured in 245 children.”

Their data showed a distinct association:

“Patients were characterized as having atopic eczema (AE); the remainder were healthy control subjects. Serum BAFF level in children with AE was significantly higher than in non-AE children or healthy controls.“

Not surprisingly considering immune function in the common mucosal barrier system, there is also evidence that B-cell activating factor is induced by airborne hypersensitivity reactions. A study published in The Journal of Allergy and Clinical Immunology documents the increased production of BAFF in the airway tissues after exposure to antigen.  The authors state:

“The objective of this study was to investigate the production of B cell-activating factor of the TNF family (BAFF), an important regulator of B cell survival and immunoglobulin class switch recombination, in bronchoalveolar lavage (BAL) fluid after segmental allergen challenge (SAC) of allergic subjects.”

They measured the amount of B cell-active cytokines including BAFF in bronchoalveolar lavage (BAL) fluid after 16 adult allergic subjects where challenged with allergens or saline. The data showed a clear result:

“BAFF protein was significantly elevated in BAL fluid after allergen challenge compared with those at saline sites…BAFF levels were also significantly correlated with other B cell-activating cytokines, IL-6 and IL-13.”

As in the gut, inflammation due to allergen exposure elevated BAFF levels. The authors conclude:

“These findings imply that exposure to antigen in the airway activates a process that stimulates the release of cytokines, including BAFF and others, that are known to promote CSR [class switch recombination = a change in antibody production by B cells] and immunoglobulin synthesis by B cells.”

Finally, B cell-activating factor expression due to gluten sensitivity deserves special mention because of the insidious and distinctively injurious nature of gluten reactions. An interesting study published in the Scandinavian Journal of Gastroenterology investigates this phenomenon, while referring to the link between celiac disease, BAFF and lymphoma. The authors state:

“The B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) was recently described as a critical survival factor for B cells, and its expression is increased in several autoimmune diseases. Abnormal production of BAFF disturbs immune tolerance allowing the survival of autoreactive B cells and participates in the progression of B-cell lymphomas. Coeliac disease (CD) is a common autoimmune disorder induced by gluten intake in genetically predisposed individuals, associated with autoantibody production and with an increased risk of lymphoma at follow-up. The purpose of this study was to investigate the possible implications of BAFF in CD.”

They examined serum BAFF levels, anti-transglutaminase (a-tTG) and endomysial antibodies in 73 patients with celiac disease confirmed by biopsy and laboratory tests before starting a gluten free diet (GFD), while using 77 blood donors as controls. Their data painted a most interesting and dramatic picture:

“Serum BAFF levels appeared to be significantly more elevated in CD patients than in controls and, compared with other autoimmune diseases where BAFF is increased, a much larger percentage (80.8%) of CD patients presented BAFF levels above the normal range. In addition, serum BAFF levels were found to correlate with a-tTG antibody levels…”

And happily…

“…there was a significant reduction of BAFF after introduction of a GFD [gluten-free diet].”

To summarize the significance for obesity and weight loss:

1. B cell-activating factor (BAFF), triggered by food hypersensitivity and other allergic reactions, is associated with inflammation .
2. BAFF induces insulin resistance; the resultant higher levels of insulin force the storage of calories of fat, promoting weight gain and obesity.
3. A sucessful and physiologically sound weight loss and maintenance program should have a strategy to control inflammation and BAFF signaling. This includes the diagnosis of food allergy or sensitivity, with special emphasis on proper screening for reactions to gluten.

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Most clinicians and many lay readers may question the reason for a post human chorionic gonadotropin (hCG) for obesity when the scientific question of its efficacy has long ago been decisively put to rest. Regrettably, there are still those who promote HCG injections for weight loss. Consider a paper published in the British Journal of Clinical Pharmacology back in 1995 in which the authors conducted a meta-analysis of earlier trials including 8 controlled and 16 uncontrolled studies:

“The trials were scored for the quality of the methods (based on four main categories: study population, interventions, measurement of effect, and data presentation and analysis) and the main conclusion of author(s) with regard to weight-loss, fat-redistribution, hunger, and feeling of well-being.”

What did the authors determine from the data presented?

“We conclude that there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight-loss of fat-redistribution, nor does it reduce hunger or induce a feeling of well-being.“

German investigators reported their examination of the available science in a paper published in in 1987 in the journal Geburtshilfe und Frauenheilkd. The authors state:

“The British physician A.T.W. Simeons described in 1954 a new method for dieting. He combined a reduction diet (500 kcal per day) with daily injections of the pregnancy hormone human chorionic gonadotropin (hCG) (125 IU i.m.). According to Simeons the patient should not lose more weight during a 4-to-6 weeks’ diet than without hCG, but the injections should facilitate to maintain the diet and to lose body weight at specific parts of the body (e.g. hip, belly, thigh).”

After noting that early descriptions of positive effects were “reports on therapeutical experiences and were not controlled studies,” they go on to state:

“In recent publications describing mostly well-documented double-blind studies authors largely reject hCG administration in dieting. Supporters of the hCG diet must prove the efficacy of this method in controlled studies according to the German Drug Law. Until then the opinion of the German steroid toxicology panel is still valid, that hCG is ineffective in dieting and should not be used.“

A few years later investigators published a paper in the South African Medical Journal reporting that…

“In a double-blind, placebo-controlled study, the effects of HCG on weight loss were compared with placebo injections.”

They examined the effects of daily intramuscular injections of saline or HCG, 6 days a week for 6 weeks, on forty obese women, all on the same diet. They also conducted a psychological profile, evaluated hunger level, measured body circumferences, took fasting blood samples and maintained food records while measuring body weight weekly. What did their data show?

“Subjects receiving HCG injections showed no advantages over those on placebo in respect of any of the variables recorded. Furthermore, weight loss on our diet was similar to that on severely restricted intake. We conclude that there is no rationale for the use of HCG injections in the treatment of obesity.”

Canadian researchers came to a similar conclusion in a paper published in the Canadian Medical Association Journal. The authors state:

“It has recently come to our attention that a number of practitioners are still using daily deep intramuscular injections of human chorionic gonadotropin (HCG) as an adjunct in the management of obesity. We condemn, in terms that cannot possibly be misconstrued, such use of HCG.“

After reviewing the evidence available at the time (1983) and listing several serious potential side-effects hypercoagulability and thromboembolism, they go so far as to assert:

“Because HCG is “therapy” in the management of obesity has been thoroughly discredited and thus rejected by the majority of the medical community, any practitioner whose patients experience undesirable side effects as a consequence of such therapy may face civil and even criminal liability.”

American scientists had demonstrated the ineffectiveness of hCG for weight reduction in a double-blind study published back in 1976 in The American Journal of Clinical Nutrition. They undertook a duplication of the original study which first suggested there may be of benefit:

“Our investigation was designed to retest the hypothesis of the efficacy of human chorionic gonadotropin (HCG) on weight reduction in obese women in a clinic setting. We sought to duplicate the Asher-Harper study (1973) which had found that the combination of 500 cal diet and HCG had a statistically significant benefit…”

Their study cohort included fifty-one women between the ages of 18 and 60 who participated in a 32- day randomized and double-blind comparison of HCG versus placebo. Each patient was given the same diet as prescribed in the Asher-Harper study. Laboratory studies were also performed at the beginning and end of the study. What did they find?

“There was no statistically significant difference in the means of the two groups in number of injections received, weight loss, percent of weight loss, hip and waist circumference, weight loss per injections, or in hunger ratings. HCG does not appear to enhance the effectiveness of a rigidly imposed regimen for weight reduction.“

A paper published more recently in the journal Obesity Reviews notes the discredited status of hCG for weight loss while commenting on the larger problem of the commercial marketing of ineffective weight loss programs:

“The increasing prevalence of obesity has been mirrored by a parallel increase in the number of commercial weight loss programmes. Research evaluating these programmes is meagre, however, compared to the numbers treated….Evaluation of commercial weight loss programmes usually progresses from testimonials, often by famous people who were successful, to uncontrolled studies of past participants evaluated either by the programme itself or by an outside entity.”

The authors further state:

“The gold standard, however, is a scientifically rigorous, controlled study of the programme conducted by an independent entity. Such a study, published in a peer-reviewed journal, can gain credibility for a programme, as it did with Slim Fast, if the results are positive, or herald the end of the programme, as it was with Simeons human chorionic gonadotropin injection clinics.“

The author of an essay recently published in the West Virginia Medical Journal presents his position under the title of “There they go again”–hCG and weight loss.” He regrets that the availability of medications on the internet exposes patients to ineffective treatments and unsafe products:

“Dr. Albrink’s review of information available in 1969 did not allow her to determine a physiologic basis for the use of hCG or any proof of immediate or long term benefit. Subsequent discoveries and clinical studies only support her impressions. Despite these facts, this form of therapy has achieved a resurgence in popularity. The difference today is that patients no longer have to rely on health care providers to prescribe their medications since internet sites allow them to obtain medications “on line”. This has potential adverse ramifications when we consider that the initial use of gonadotropins derived from the human pituitary was discontinued due to the iatrogenic transmission of Creutzfeld-Jakob disease…Systematic information has been obtained and has shown lack of evidence for the benefit of this therapy. “

The body of evidence on hCG for weight loss is summed up in  a comment in The Medical Letter Online:

“Use of hCG as an adjunct to diet goes back to the 1950’s, when a British physician named Simeons recommended daily injections of the hormone combined with a 500 kcal diet, and such use came to be known as the Simeons method. One double-blind study after another throughout the second half of the 20th century found hCG to be worthless for weight loss or maintenance.“

An interesting question remains. Human chorionic gonadotropin does have legitimate medical uses and is well known to increase testosterone levels. Since testosterone therapy given to hypogonadal men (men with low testosterone levels) has been shown to improve body composition, why not hCG? A fascinating study published in the journal Gynecological Endocrinology offers insight. The authors state:

“The aim of this study was to monitor serum leptin concentrations after altering the levels of testosterone, by intramuscular administration of human chorionic gonadotropin (hCG), in eugonadal men.”

“Eugonadal” means their study subjects had normal testicular function. They monitored hCG, testosterone and leptin levels after intramuscular administration of a dose of 5000 IU hCG in thirty men. Blood samples were collectedafter an overnight fast for CG, testosterone and leptin levels, and a dose of 5000 IU hCG was administered intramuscularly immediately after. They kept testing the blood at 24-h intervals for a period of 7 days. What did their data show?

“Our results support the view that hCG administration in eugonadal men does not influence serum leptin levels. Moreover, a short-term increase of serum testosterone levels, after one dose of hCG, is not sufficient to affect and modify leptin secretion mechanisms in vivo.”

Since a significant correlation between body mass index and serum leptin is well established, the failure to influence leptin may explain, at least in part, why hCG is not effective for weight loss.

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