Hypothalamic PKA regulates leptin sensitivity and adiposity

• Published in: Nature communications 2015-09, Vol.6 (1), p.8237-8237, Article 8237
• Main Authors: Yang, Linghai, McKnight, G. Stanley
• Format: Article
• Language: English
• Subjects: 13; 14; 38; 631/378/1488/1562; 631/378/1488/393; 631/80/458/1733; 631/80/86; 64/60; 82; 82/29; 82/51; 82/80; 96; 96/1; 96/44; 96/95; Adiposity - genetics; Agouti-Related Protein - metabolism; Animals; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit - genetics; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Diet, High-Fat; Feedback, Physiological; Humanities and Social Sciences; Hypothalamus - metabolism; Janus Kinases - metabolism; Leptin - metabolism; Leptin - pharmacology; Mice; Mice, Knockout; multidisciplinary; Neurons - metabolism; Neuropeptide Y - metabolism; Obesity - genetics; Phosphorylation; Pro-Opiomelanocortin - genetics; Pro-Opiomelanocortin - metabolism; Receptors, Leptin - metabolism; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Signal Transduction; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9237

Mice lacking the RIIβ regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIβ knockout (KO) mice have enhanced sensitivity to leptin’s effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIβ KO mice. During fasting, RIIβ–PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIβ KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIβ KO mice. Our findings suggest that RIIβ–PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin. Mice lacking RIIβ, a regulatory subunit of protein kinase A, are lean and resistant to diet-induced obesity. Here, the authors show that RIIβ regulates leptin sensitivity, acting as a physiological brake on leptin responsiveness and the duration of leptin signalling in the hypothalamus.