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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A fascinating report just published in the journal Science further illustrates the biological power of imagery, in this case the ability to decrease the desire to eat a particular food by first  repeatedly imagining that you have eaten it. The authors state:

“People believe that thinking about a desirable food or drug sensitizes one to it, increasing their hedonic response to the stimulus. Indeed, picturing oneself eating a delicious steak elicits an increase in salivation and the desire to eat it, and imagining the sight or smell of a burning cigarette increases smokers’ craving.”

They note, however, that this…

“…seems to contradict decades of research examining the overlap between direct perception and mental imagery.”

Furthermore…

“Perception and mental imagery differ in their source (the senses and memory, respectively), but there is great overlap within modalities. Both engage similar neural machinery and similarly affect emotions, response tendencies, and skilled motor behavior. The thought of a spider crawling across one’s leg can produce the same increases in perspiration and heart rate that would result from a spider’s actual presence. Even the mere simulation of a motor skill can result in an improvement in its subsequent performance.“

Therefore…

“Because perception and mental imagery tend to elicit similar responses, one would expect that thinking about the consumption of a stimulus should habituate one to it…Habituation denotes the decreased physiological and behavioral responses induced by extended or repeated exposure to a stimulus. A 10th bite of chocolate, for example, is desired less than the first bite. People habituate to a wide range of stimuli, from the brightness of a light to their income.”

So why would exposure to a stimulus sometimes elicit sensitization (with an increase in desire) and sometimes habituation? The authors state:

“…having participants vividly imagine a single exposure to a stimulus…is more analogous to the initial exposure…that whets the appetite and induces sensitization than to the repeated experience of a stimulus necessary to engender habituation.”

By contrast…

“We suggest that mentally simulating an experience that is more analogous to repeated exposure (such as repeatedly imagining the consumption of units of a food) might engender habituation to the stimulus.“

They conducted five different experiments designed to test whether the repeated mental simulation by only imagining eating a food could engender habituation and reduce the subsequent consumption of that food. What did their data show?

“We demonstrated that habituation to a food item can occur even when its consumption is merely imagined. Five experiments showed that people who repeatedly imagined eating a food (such as cheese) many times subsequently consumed less of the imagined food than did people who repeatedly imagined eating that food fewer times, imagined eating a different food (such as candy), or did not imagine eating a food. They did so because they desired to eat it less, not because they considered it less palatable. These results suggest that mental representation alone can engender habituation to a stimulus.”

An accompanying editorial in the same journal notes:

“The findings should have practical applications, says Frances McSweeney, a psychologist at Washington State University, Pullman. One possible strategy for weight watchers might be to spend a few minutes before each meal imagining eating exactly the foods they’re about to consume, she says. This type of mental exercise might also help counter sudden cravings between meal times, adds Suzanne Higgs, a psychologist at the University of Birmingham in the United Kingdom…Ironically, Morewedge says, many diets urge people to suppress thoughts of the foods they crave.“

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More research recently published in the Archives of Internal Medicine further validates the power of waist circumference measurements to predict death from all causes. This study provides evidence that its accuracy is far superior to body mass index (BMI).

“Waist circumference (WC), a measure of abdominal obesity, is associated with higher mortality independent of body mass index (BMI). Less is known about the association between WC and mortality within categories of BMI or for the very high levels of WC that are now common.”

The authors examined the association between WC and mortality among 48 500 men and 56 343 women between 1997 and 2006, during which 9315 men and 5332 women died. Considering the adverse metabolic and hormonal activity of visceral (intra-abdominal versus subcutaneous) fat, their data is not surprising:

“After adjustment for BMI and other risk factors, very high levels of WC were associated with an approximately 2-fold higher risk of mortality in men and women…The WC was positively associated with mortality within all categories of BMI.”

Very high levels of WC means 47 inches for men and 43 inches for women. Waist circumference is a more reliable indicator than weight or BMI. If you’re losing weight without your WC getting smaller, you’re probably losing more muscle than fat. As the authors state in their conclusion:

“These results emphasize the importance of WC as a risk factor for mortality in older adults, regardless of BMI.”

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Phytochemicals occur naturally in plants, especially richly colored vegetables and fruits. This interesting study reports that a Phytochemical Index (PI), derived from the proportional amount of phytochemical-rich foods in the subjects’ diets, correlated with weight-gain, waist circumference, waist-to-hip ratio and plasma oxidative stress (linked to inflammation). “The PI score was a significant contributor to yearly weight gain.” This confirms an additional benefit from a diet whose carbohydrate portion is mainly from low-glycemic vegetables and fruits.

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