Understanding obesity as an inflammatory condition

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.