Inflammasome is a central player in the induction of obesity and insulin resistance

Abstract

Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in proinflammatory cytokine production. Both microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3, resulting in caspase-1 activation and production of proinflammatory cytokines IL-1β and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1 were resistant to the development of high-fat diet-induced obesity, which correlated with protection from obesityinduced insulin resistance. Furthermore, hepatic triglyceride content, adipocyte size, and macrophage infiltration in adipose tissue were all reduced in mice deficient in inflammasome components. Monocyte chemoattractant protein (MCP)-1 is a key molecule that mediates macrophage infiltration. Indeed, defective inflammasome activation was associated with reduced MCP-1 production in adipose tissue. Furthermore, plasma leptin and resistin that affect energy use and insulin sensitivity were also changed by inflammasome-deficiency. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance, and suggest inhibition of the inflammasome as a potential therapeutic strategy.

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

“…Lipotoxic‐saturated fatty acids activate the inflammasome pathway in hepatocytes and the subsequent release of pro‐inflammatory cytokines, such as IL‐1β and IL‐18 26, 27. NLRP3 is significantly up‐regulated in patients with NASH,28 and inhibition or knockdown of the inflammasome components reduces insulin resistance, steatosis, and fibrosis 29, 30, 31. Lee et al showed that the PPARδ ligand GW501516 inhibits the activation of the inflammasome pathway in vivo and in vitro in HepG2 cells 32.…”

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

“…These cells are mainly CD4 + and CD8 + effector memory T (T EM ) cells and contribute to obesity-associated inflammation of WAT (63,64). Classically activated M1 macrophages within fat depots are also causally linked to the development of obesity-induced adipose tissue inflammation and insulin resistance (65)(66)(67)(68)(69)(70)(71). Importantly, Kv1.3 regulates membrane potential and calcium signaling in T EM cells, and ShK-186 suppresses cytokine production, proliferation, and in vivo migration and activation of these cells (16)(17)(18)(19)(20)(21).…”

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…Accumulating evidences also give to NLRP3 inflammasome a central role in obesity-induced insulin resistance [33,55,56]. The expression of NLRP3 inflammasome components, the activity of caspase-1 and the levels of IL-1β are increased in adipose tissue, mainly in macrophages, of obese mice and humans and directly correlate with insulin resistance, features of the metabolic syndrome and severity of T2DM [33,56].…”

“…Moreover its inhibition has shown to have pleiotropic effects combining improved insulin signaling in adipose tissue, liver and skeletal muscle, and increased insulin secretion in the pancreas [55,56].…”