C1q/TNF-related Protein 6 (CTRP6) Links Obesity to Adipose Tissue Inflammation and Insulin Resistance

J Biol Chem. 2017 Sep 8;292(36):14836-14850. doi: 10.1074/jbc.M116.766808. Epub 2017 Jul 18.

Abstract

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.

Keywords: adipose tissue; inflammation; insulin resistance; macrophage; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipokines / deficiency
  • Adipokines / metabolism*
  • Adipose Tissue / metabolism*
  • Animals
  • Cells, Cultured
  • Collagen / metabolism*
  • Disease Models, Animal
  • Humans
  • Inflammation / metabolism*
  • Insulin Resistance*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Obesity / metabolism*
  • RAW 264.7 Cells

Substances

  • Adipokines
  • C1qTNF6 protein, human
  • CTRP6 protein, mouse
  • Collagen