Obesity is a major risk factor for many diseases, including type 2 diabetes, cardiovascular disease, and some types of cancers, making it the second leading preventable cause of death in the U.S. Prevention and treatment of obesity are difficult, largely because changes in food intake and body weight are associated with compensatory changes in energy expenditure, which keep body weight at the original “set point”. In other words, we need to increase (or at least maintain) energy expenditure, in addition to lifestyle interventions and medications, to treat obesity.
Brown adipose tissue (BAT) and “brown-like” beige adipocytes in white adipose tissue (WAT) burn fat and dissipate chemical energy as heat (thermogenesis), largely through uncoupling protein 1 (UCP1). The potential of brown and beige adipocytes as anti-obesity targets attracts extensive interest. Many intrinsic proteins and pathways have been identified to be critical for the development, regulation, and pathophysiology of brown and beige adipocytes (Fig. 1).
The research in our laboratory aims to identify extrinsic and intrinsic factors that govern the thermogenic program and to understand how themogenic adipocytes modulate systemic metabolism.
Stem cell factor (SCF)
Serum levels of SCF increase in conditions where energy expenditure is increased in a compensatory manner such as feeding, cold exposure, and obesity. By analyzing gain- and loss-of-function mouse models, we found that SCF and its receptor Kit promote Ppargc1a gene transcription, mitochondrial biogenesis and energy expenditure in BAT, thus protecting mice from diet-induced obesity. We propose that SCF is a “satiety hormone” that acts peripherally to counteract obesity.
Hypothalamic AgRP neurons
Caloric restriction and fasting reduce body temperature and thermogenesis. We demonstrated that hunger-induced hormone ghrelin and hypothalamic AgRP neurons suppress the activity of beige fat. Mechanistically, ghrelin activates the O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in AgRP neurons, which promotes neuronal excitability, inhibits white adipose tissue browning, and leads to weight-gain in mice. These two studies have demonstrated how hormones regulate the expenditure arm of the energy balance equation in order to maintain homeostasis in feast and famine (Fig. 2).
1. Yang, X, Ruan HB. (2015). Neuronal control of adaptive thermogenesis. Frontiers in Endocrinology. 6:149.
2. Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, Zhang K, Yin R, Wu J, Horvath TL, Yang X. (2014). O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell. 159(2): 306-317.
3. Huang Z*, Ruan HB*, Xian L, Chen W, Jiang S, Song A, Wang Q, Shi P, Gu X, Gao X. (2014) The stem cell factor/Kit signaling pathway regulates mitochondrial function and energy expenditure. Nature Communications. 5:4282. (*, Equal contribution).