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Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet-induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-α. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin-stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance.

CTRP4 is a unique member of the C1q family, possessing two tandem globular C1q domains. Its physiological function is poorly defined. Here, we show that CTRP4 is an evolutionarily conserved, ∼34-kDa secretory protein expressed in the brain. In human, mouse, and zebrafish brain, CTRP4 expression begins early in development and is widespread in the central nervous system. Neurons, but not astrocytes, express and secrete CTRP4, and secreted proteins form higher-order oligomeric complexes. CTRP4 is also produced by peripheral tissues and circulates in blood. Its serum levels are increased in leptin-deficient obese (ob/ob) mice. Functional studies suggest that CTRP4 acts centrally to modulate energy metabolism. Refeeding following an overnight fast induced the expression of CTRP4 in the hypothalamus. Central administration of recombinant protein suppressed food intake and altered the whole-body energy balance in both chow-fed and high-fat diet-fed mice. Suppression of food intake by CTRP4 is correlated with a decreased expression of orexigenic neuropeptide (Npy and Agrp) genes in the hypothalamus. These results establish CTRP4 as a novel nutrient-responsive central regulator of food intake and energy balance.

Cells turn on autophagy, an intracellular recycling pathway, when deprived of nutrients. How autophagy is regulated by hormonal signals in response to major changes in metabolic state is not well understood. Here, we provide evidence that myonectin (CTRP15), a skeletal muscle-derived myokine, is a novel regulator of cellular autophagy. Starvation activated liver autophagy, whereas nutrient supplementation following food deprivation suppressed it; the former and latter correlated with reduced and increased expression and circulating levels of myonectin, respectively, suggestive of a causal link. Indeed, recombinant myonectin administration suppressed starvation-induced autophagy in mouse liver and cultured hepatocytes, as indicated by the inhibition of LC3-dependent autophagosome formation, p62 degradation, and expression of critical autophagy-related genes. Reduction in protein degradation is mediated by the PI3K/Akt/mTOR signaling pathway; inhibition of this pathway abrogated the ability of myonectin to suppress autophagy in cultured hepatocytes. Together, our results reveal a novel skeletal muscle-liver axis controlling cellular autophagy, underscoring the importance of hormone-mediated tissue cross-talk in maintaining energy homeostasis.