A Hypothalamic Phosphatase Switch Coordinates Energy Expenditure with Feeding

• Published in: Cell metabolism Vol. 26; no. 2; pp. 375 - 393.e7
• Main Authors: Dodd, Garron T., Andrews, Zane B., Simonds, Stephanie E., Michael, Natalie J., DeVeer, Michael, Brüning, Jens C., Spanswick, David, Cowley, Michael A., Tiganis, Tony
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017
• Subjects: Agouti-Related Protein - genetics; Agouti-Related Protein - metabolism; AgRP; Animals; Beige adipocyte; Diet-induced thermogenesis; Eating - psychology; Energy expenditure; Energy Metabolism - physiology; Hypothalamus; Hypothalamus - metabolism; Insulin; Mice; Mice, Transgenic; Neuropeptide Y - genetics; Neuropeptide Y - metabolism; Obesity; Obesity - genetics; Obesity - metabolism; Protein tyrosine phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - biosynthesis; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; TCPTP; White adipose tissue browning; Obesity; TCPTP; White adipose tissue browning; Protein tyrosine phosphatase; Energy expenditure; Hypothalamus; AgRP; Insulin; Beige adipocyte; Diet-induced thermogenesis
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.07.013

Beige adipocytes can interconvert between white and brown-like states and switch between energy storage versus expenditure. Here we report that beige adipocyte plasticity is important for feeding-associated changes in energy expenditure and is coordinated by the hypothalamus and the phosphatase TCPTP. A fasting-induced and glucocorticoid-mediated induction of TCPTP, inhibited insulin signaling in AgRP/NPY neurons, repressed the browning of white fat and decreased energy expenditure. Conversely feeding reduced hypothalamic TCPTP, to increase AgRP/NPY neuronal insulin signaling, white adipose tissue browning and energy expenditure. The feeding-induced repression of hypothalamic TCPTP was defective in obesity. Mice lacking TCPTP in AgRP/NPY neurons were resistant to diet-induced obesity and had increased beige fat activity and energy expenditure. The deletion of hypothalamic TCPTP in obesity restored feeding-induced browning and increased energy expenditure to promote weight loss. Our studies define a hypothalamic switch that coordinates energy expenditure with feeding for the maintenance of energy balance. [Display omitted] •Diurnal changes in hypothalamic TCPTP coordinate feeding with energy expenditure•Feeding represses hypothalamic TCPTP to increase energy expenditure•TCPTP inhibits insulin signaling in AgRP neurons to repress energy expenditure•Insulin signaling in AgRP neurons increases the browning of white fat Changes in food intake must be matched by commensurate changes in energy expenditure for body weight maintenance. Dodd et al. show that diurnal fluctuations of the insulin receptor phosphatase TCPTP coordinate insulin signaling in AgRP/NPY neurons, so that WAT browning is increased in response to feeding and repressed during fasting.