CRTC1 Maintains Metabolic Homeostasis and Protects Against Partial Lipodystrophy & Insulin Resistance by Regulating Diet‐Responsive White Adipose Tissue Remodeling

Abstract

Humans evolved the ability to store lipid in specialized tissue called adipose to support survival. Adipose provides an energy depot that can be quickly mobilized in response to acute stress (fight‐or‐flight), for reproduction and during extended fasting. Defects in white adipose tissue (WAT) function, and inability of the WAT depots to expand in the context of overnutrition, will lead to ectopic lipid accumulation in the muscle and liver triggering serious metabolic diseases such as type 2 diabetes (T2D).Our data demonstrate that CREB Regulated Transcription Coactivator 1 (CRTC1) gene function is important in maintaining metabolic fitness. CRTC1 is expressed primarily in the hypothalamus where it controls satiety in response to cAMP and Ca2+ signals. Recent studies identified small nucleotide polymorphisms (SNPs) in the human gene locus CRTC1 that correlate with decreased adiposity in the context of obesity, indicating that CRTC1 may play an important role in adipose function. Here, we describe a previously unknown role of CRTC1 in the regulation of epididymal WAT (eWAT) expansion in response to high fat diet (HFD).Basal CRTC1 protein expression in eWAT is low compared to that in the brain, yet specifically increased in eWAT in response to HFD. Loss of CRTC1 by whole‐body germline knockout (CRTC1 KO mice), acute antisense oligonucleotide knockdown in WAT (CRTC1 ASO mice), and tissue‐specific germline knockout in adipose tissue (CRTC1 AKO mice) results in impaired HFD‐responsive eWAT expansion, observed as a ~50% decrease in eWAT size. Diminished capacity for eWAT expansion coincides with elevated lipid accumulation in liver and muscle, hyperglycemia, hyperinsulinemia and glucose intolerance in these animals relative to wildtype or control.CRTC1 knockdown by adenoviral shRNA decreased glucose uptake, increased lipolysis and impeded expression of the key adipogenesis marker PPARγ in differentiated 3T3‐L1 adipocytes. Animal models with decreased CRTC1 expression (CRTC1 KO, ASO and AKO) also exhibited decreased PPARγ expression in eWAT but only on HFD, suggesting that CRTC1 is required for diet‐responsive eWAT remodeling and for maintaining a differentiated state in adipocytes. Supportive of this hypothesis, we observed significantly decreased eWAT FGF1 mRNA expression, plasma FGF1 and WAT FGF1 levels in HFD‐fed animal models of CRTC1 loss relative to control. FGF1 plays a major role in eWAT remodeling and expansion in response to diet: our data indicate that CRTC1 is required for HFD‐mediated upregulation of FGF1. Together, our findings reveal a regulatory axis that is essential for eWAT remodeling and expansion, and that leads to ectopic lipid deposition and insulin resistance when perturbed. Understanding how CRTC1 regulates FGF1 and impacts the PPARγ pathway in eWAT will provide important insights into adipocyte function and into how eWAT expansion is modulated to maintain metabolic homeostasis, allowing identification of new potential targets to treat diseases such as T2D.Support or Funding InformationLife Science Research Foundation Fellowship, Sponsor: Gilead Sciences Inc.; R01 DK083834, PI: Marc Montminy