Inflammatory mechanisms linking obesity and metabolic disease (original) (raw)

The precise triggers of obesity-associated inflammation are poorly understood, and may also differ from tissue to tissue. While obesity is closely associated with increased inflammatory markers in liver, adipose tissue, skeletal muscle, pancreatic islets, and brain, the precise temporal relationships between these events in rodents or obese humans remain uncertain. Kanakadurga Singer and Carey Lumeng review the initiating events in obesity-induced inflammation in the context of human development, many of which are sustained into adulthood (11). Numerous mechanisms have been investigated in rodent models of dietary and genetic obesity (12, 13). For example, obesity gives rise to increased intestinal permeability, which results in higher circulating levels of LPS from intestinal Gram-positive bacterial species (14). This gut-derived LPS may initiate an inflammatory cascade via activation of pattern recognition receptors (PRRs) such as TLR4 in fat cells. Similar events are likely to occur in liver. Consistent with this theory, increased circulating LPS is positively correlated with T2D in humans (15). However, intestinal-derived LPS is a systemic circulating factor, and so is probably an amplifier of inflammatory processes, rather than a tissue-specific triggering mechanism. Daniel Winer, Tony Lam, and colleagues described the changes in the intestinal immune system that may influence systemic immunity and glucose metabolism, contributing to the pathology of obesity and diabetes (16).

Different lipid species that are elevated due to diet or obesity may also contribute to inflammation. Free fatty acids can promote inflammation by indirectly binding to TLR4 and TLR2 through the adaptor protein fetuin A, resulting in NF-κB and JNK1 activation (15). Once activated, these pathways can increase the synthesis and secretion of chemokines such as monocyte chemoattractant protein–1 (MCP1) from adipocytes or hepatocytes, leading to infiltration of proinflammatory macrophages. Parenthetically, there are lipid species such as omega-3 and -6 fatty acids that serve anti-inflammatory roles (17).

There is also evidence that hypoxia develops as adipose tissue expands due to relative underperfusion of the enlarging adipose tissue or increased oxygen consumption (18), and cellular hypoxia may in turn initiate inflammation by inducing the HIF1 gene program. Indeed, genetic deletion of adipocyte HIF1 prevents obesity-induced inflammation and insulin resistance (18). Exposure of adipose tissue in culture to hypoxic conditions can induce upregulation of numerous inflammatory genes (19). Immunostaining of adipose tissue from obese rodents or humans reveals that areas of hypoxia are correlated with regions displaying infiltration of macrophages. Likewise, adipocyte necrosis is closely associated with the development of inflammation.

Another potential mechanism underlying inflammation is mechanical stress on the fat cell. Adipocytes interact with their extracellular matrix (ECM) via pathways that govern differentiation and expansion in response to obesity (20). Expansion of adipocytes in the ECM-fixed environment can elicit various mechanical stresses on these cells. Indeed, adipocyte knockout of collagen genes (21) or the collagenases that degrade collagen, particularly MMP14, has a major impact on lipid synthesis, storage, and energy metabolism (22).

In addition to metabolic dysfunction in the peripheral organs, obesity and obesity-associated inflammation have also been linked to alterations in brain function, particularly in areas that regulate energy homeostasis and systemic metabolism. The hypothalamus controls neuroendocrine circuits, including the melanocortin system, that regulate feeding behavior and energy expenditure. High-fat/high-calorie diets have been shown to induce inflammatory processes in the hypothalamus prior to the induction of these events in the peripheral tissues. Alexander Jais and Jens Brüning describe the contributions of different neuronal and non-neuronal cell types to hypothalamic inflammation (23).