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Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8(+) T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII(+) cells exhibited a similar phenotype in DIO as CD40(-/-) mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII(+) cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII(+) cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII(+) cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.

Obese adipose tissue (AT) inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, compared with lean AT. In addition, C5a was present in obese AT in the proximity of macrophage-rich crownlike structures. C5aR-sufficient and -deficient mice were fed a high-fat diet (HFD) or a normal diet (ND). C5aR deficiency was associated with increased AT weight upon ND feeding in males, but not in females, and with increased adipocyte size upon ND and HFD conditions in males. However, obese C5aR(-/-) mice displayed improved systemic and AT insulin sensitivity. Improved AT insulin sensitivity in C5aR(-/-) mice was associated with reduced accumulation of total and proinflammatory M1 macrophages in the obese AT, increased expression of IL-10, and decreased AT fibrosis. In contrast, no difference in β cell mass was observed owing to C5aR deficiency under an HFD. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and thereby to AT dysfunction and development of AT insulin resistance.

Highlights: [•] Complement plays a major role in metabolic organs and in metabolic diseases. [•] Complement components affect insulin secretion and adipocyte maturation. [•] Complement contributes to the pathogenesis of T1DM and T2DM. [•] Complement regulates liver inflammation and steatosis. [ABSTRACT FROM AUTHOR]