Hypothalamic PKA regulates leptin sensitivity and adiposity.

Mice lacking the RIIβ regulatory subunit of cyclic AMP-dependent protein kinase A 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 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/duanyu18133 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIβ KO mice. During fasting, 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 activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIβ KO mice. Our findings suggest that RIIβ-duanyu1529 modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin.

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