Metabolic programming in tissue development, homeostasis and disease

The maintenance of metabolic homeostasis depends on proper programming of nutrient and energy metabolism in tissues. Adult tissues are highly specialized in their metabolic functions, yet at the same time exhibit a remarkable degree of plasticity. By dissecting the molecular and genetic underpinnings of metabolic programming, we gain insights into how energy metabolism is specified during tissue development, how nutrient signaling impinges on key metabolic pathways, and how altered nutrient and energy metabolism leads to obesity, type 2 diabetes, and fatty liver disease. 

We have discovered epigenetic mechanisms mediated by chromatin-remodeling complexes that drive the formation and function of oxidative and glycolytic muscle. We have expanded the regulatory code beyond protein factors and revealed long non-coding RNAs (lncRNAs) in the control of brown and beige adipocyte differentiation and metabolism. We have gained insights into the mechanisms that govern circadian control of metabolic rhythms.

Metabolic crosstalk via secreted factors

Cells and tissues do not exist in isolation in the body; instead, they are constantly exposed to the ebb and flow of nutrients and hormones and release factors that serve as metabolic signals. By discovering new secreted hormones, we illustrate the concept that a distributed endocrine signaling network serves important functions in the regulation of metabolic physiology and homeostasis. We combine global profiling and single-cell analysis to identify novel ligands and receptors, investigate their role in metabolic crosstalk and explore the potential of developing biologic therapeutics for the treatment of metabolic disease.

Journal Covers

"On the cover: Skeletal muscle senses blood sugar levels and engages a nutrient signaling cascade to maintain glucose homeostasis. In this issue of Molecular Cell, Meng et al. (pp. 332–344) discovered a glucose sensing pathway in skeletal myocytes that promotes muscle glucose disposal through insulin-independent AKT activation. This pathway is engaged by the sulfonylurea class of anti-diabetic drugs and contributes to their glucose-lowering effects. This study illustrates the concerted action of hormonal (insulin) and nutrient (glucose) signaling in skeletal muscle in systemic glucose homeostasis. Artwork by Stephanie King."

"In this issue of the JCI, Guo et al. demonstrate a critical role for NRG4, an adipose tissue-derived endocrine factor, in gating the transition from hepatic steatosis to nonalcoholic steatohepatitis (NASH). NRG4 signaling in hepatocytes protects against cell death and symptoms of NASH, including liver injury, inflammation, and fibrosis. The cover image depicts adipose tissue, the source of NRG4, with lipid droplets indicated in green and cell membranes in red. Image credit: Guo-Xiao Wang and Stephanie King."