SUMMARY Omega-3 fatty acids (ω-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here we show that the G protein-coupled receptor 120 (GPR120) functions as an ω-3 FA receptor/sensor. Stimulation of GPR120 with ω-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high fat diet with or without ω-3 FA supplementation. The ω-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional ω-3 FA receptor/sensor and mediates potent insulin sensitizing and anti-diabetic effects in vivo by repressing macrophage-induced tissue inflammation.

SUMMARY Obese adipose tissue is characterized by infiltration of macrophages. We and others recently showed that a specific subset of macrophages is recruited to obese adipose and muscle tissue. This subset expresses CD11c and produces high levels of pro-inflammatory cytokines that are linked to the development of obesity-associated insulin resistance. We used a conditional cell ablation system, based on transgenic expression of the diphtheria toxin receptor under the control of the CD11c promoter, to study the effects of depletion of CD11c+ cells in obese mouse models. Our results show that CD11c+ cell depletion results in rapid normalization of insulin sensitivity. Furthermore, CD11c+ cell ablation leads to a marked decrease in inflammatory markers, both locally and systemically, at the level of gene expression and protein levels. Together, these results indicate that these CD11c+ cells are a potential therapeutic target for treatment of obesity-related insulin resistance and type II diabetes.

OBJECTIVETissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions.RESEARCH DESIGN AND METHODSWe fed a high-fat diet (HFD) to wild-type mice and three different immuno-compromised mouse models (lymphocyte-deficient Rag1 knockout, macrophage-depleted, and hematopoietic cell-specific Jun NH2-terminal kinase–deficient mice) and measured the time course of changes in macrophage content, inflammatory markers, and lipid accumulation in adipose tissue, liver, and skeletal muscle along with systemic insulin sensitivity.RESULTSIn wild-type mice, body weight and adipose tissue mass, as well as insulin resistance, were clearly increased by 3 days of HFD. Concurrently, in the short-term HFD period inflammation was selectively elevated in adipose tissue. Interestingly, however, all three immuno-compromised mouse models were not protected from insulin resistance induced by the short-term HFD. On the other hand, lipid content was markedly increased in liver and skeletal muscle at day 3 of HFD.CONCLUSIONSThese data suggest that the initial stage of HFD-induced insulin resistance is independent of inflammation, whereas the more chronic state of insulin resistance in established obesity is largely mediated by macrophage-induced proinflammatory actions. The early-onset insulin resistance during HFD feeding is more likely related to acute tissue lipid overload.

Summary Insulin resistance, tissue inflammation and adipose tissue dysfunction are features of obesity/Type 2 diabetes. Accordingly, we generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knock-out (AKO) mice to investigate the function of NCoR in adipocyte biology and glucose/insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and euglycemic clamp studies demonstrated enhanced insulin sensitivity in liver, muscle and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies a novel function of NCoR as an adaptor protein which enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD treated state.

In adipose, muscle, liver and macrophages, signaling by the nuclear receptor PPARγ is a determinant of insulin sensitivity and this receptor mediates the insulin–sensitizing effects of thioazolidinediones (TZDs)1-4. Since PPARγ is also expressed in neurons5, we generated mice with neuron–specific Pparγ knockout (Pparγ BKO) to determine whether neuronal PPARγ signaling contributes to either weight gain or insulin resistance. During high fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparγ BKO mice, resulting in reduced weight gain. When treated with the TZD rosiglitazone, Pparγ BKO mice were resistant to rosiglitazone–induced hyperphagia and weight gain and, relative to rosiglitazone–treated controls, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the effect of rosiglitazone treatment to increase hepatic insulin sensitivity during HFD feeding was completely abolished in Pparγ BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPARγ signaling to limit thermogenesis and increase food intake. Neuronal PPARγ signaling is also required for the hepatic insulin sensitizing effects of TZDs.