Transcriptional fine-tuning of adipocyte metabolism

Abstract

The evolution of adipocytes provides mammals with a dedicated compartment for efficient energy storage in the form of triglyceride. Fat cells possess the biochemical machinery to convert glucose and free fatty acids (FFAs) into triglyceride (lipogenesis) during times of nutrient excess. When energy demand is high, triglycerides can be catabolized to FFAs (lipolysis). FFAs released into circulation can be used to provide fuel to cells in times of nutrient deprivation. FFAs within adipocytes can be further oxidized to generate heat through the process of adaptive thermogenesis. These anabolic and catabolic programs are highly integrated and coordinated to match nutrient availability with energy demand. Importantly, an imbalance in these programs leads to dysregulated lipid metabolism and metabolic disease. Our prior studies identified the nucleosome remodeling and deacetylase (NuRD) corepressor complex as a binding partner of key transcriptional regulators controlling the thermogenic gene program of adipocytes. The physiological importance of this complex in fat cells remains unknown. To address this, we have generated a genetic Tet-On mouse model that allows for inducible adipocyte-specific inactivation of Chd4 (Chd4iAKO mice) in the presence of doxycycline. Loss of CHD4, a primary catalytic component of the NuRD complex, leads to loss of NuRD complex activity. I find that the loss of the adipocyte CHD4-dependent NuRD complex leads to a striking upregulation of key genes driving both anabolic and catabolic pathways of lipid metabolism, including genes that might elicit futile energy cycling. Explanted tissues from chow-fed Chd4iAKO mice exhibit heightened basal and stimulated lipolysis. Acute cold exposure or pharmacological β3-adrenergic receptor agonism triggers substantial inguinal WAT inflammation, presumably due to hyper-stimulated lipolysis. Notably, inducible deletion of Chd4 in adipocytes has strong effects on body weight. Chd4 inactivation at the onset of high fat diet feeding (HFD) leads to increased energy expenditure and confers resistance to diet-induced obesity. Inactivation of Chd4 in mice with obesity (after 10+ weeks of HFD feeding) leads to gradual weight loss. However, in both cases, Chd4iAKO mice exhibit insulin resistance that is associated with expanded liver mass and ectopic lipid deposition. Together, our data highlight the importance of chromatin regulation in fine-tuning the balance between anabolic and catabolic programs in adipocytes. Moreover, our data further underscore the detrimental metabolic consequences of lipolysis, despite potential benefits to body weight and adiposity.