title: Hypothalamic PKA regulates leptin sensitivity and adiposity.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Washington School of Medicine, 1959 North East Pacific Street, Box 357280, Seattle, Washington 98195, USA.
authors.forename: Linghai
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, University of Washington School of Medicine, 1959 North East Pacific Street, Box 357280, Seattle, Washington 98195, USA.
authors.forename: G Stanley
authors.initials: GS
authors.lastname: McKnight
mesh_terms: D050154:Adiposity / Q000235:genetics*; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D025461:Feedback, Physiological; D007031:Hypothalamus / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D020738:Leptin; D009478:Neuropeptide Y; D012333:RNA, Messenger; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C515447:leptin receptor, mouse; D011333:Pro-Opiomelanocortin; D053612:Janus Kinases; D017868:Cyclic AMP-Dependent Protein Kinases