Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice

Abstract

Normal food intake and body weight homeostasis require the direct action of leptin on hypothalamic proopiomelanocortin (POMC) neurons. It has been proposed that leptin action requires PI3K activity. We therefore assessed the contribution of PI3K signaling to leptin's effects on POMC neurons and organismal energy balance. Leptin caused a rapid depolarization of POMC neurons and an increase in action potential frequency in patch-clamp recordings of hypothalamic slices. Pharmacologic inhibition of PI3K prevented this depolarization and increased POMC firing rate, indicating a PI3K-dependent mechanism of leptin action. Mice with genetically disrupted PI3K signaling in POMC cells failed to undergo POMC depolarization or increased firing frequency in response to leptin. Insulin's ability to hyperpolarize POMC neurons was also abolished in these mice. Moreover, targeted disruption of PI3K blunted the suppression of feeding elicited by central leptin administration. Despite these differences, mice with impaired PI3K signaling in POMC neurons exhibited normal long-term body weight regulation. Collectively, these results suggest that PI3K signaling in POMC neurons is essential for leptin-induced activation and insulin-induced inhibition of POMC cells and for the acute suppression of food intake elicited by leptin, but is not a major contributor to the regulation of long-term organismal energy homeostasis.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…Our findings indicate a dissociated role of distinct PI3K catalytic subunits downstream of leptin signaling, which has also been suggested by studies using chemically defined hypothalamic neurons (14, 20, 21). The metabolic similarities between mice with deletion of PI3K and those with deletion of PTEN in LR cells were intriguing (14,20,21). PTEN is a phosphatase associated with conversion of PIP3 to PIP2, resulting in PI3K inactivation (40).…”

“…Enhanced leptin sensitivity in adult LR Δα mice. PI3K signaling in POMC neurons is required for the acute effects of leptin on food intake (4,5,20). To assess if PI3Kα in LR cells is required for the acute anorexigenic effects of leptin, overnight fasted adult LR Δα and α fl control mice were injected with i.p.…”

“…neurons has suggested the existence of dissociated effects of both subunits in energy balance and glucose homeostasis (16,(20)(21)(22), but, again, whether these responses are associated with leptin or insulin signaling has not been demonstrated.…”

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

“…In addition, leptin directly governs glucose homeostasis, mainly by activating cognate leptin receptors (LEPRs) in neurons within the hypothalamic arcuate nucleus (ARH) (17)(18)(19)(20). Interestingly, leptin and insulin share similar intracellular signaling pathways in hypothalamic neurons, such as the PI3K signaling cascade (21,22). Furthermore, leptin enhances insulin sensitivity in insulin-resistant rodents and humans (19,20,23,24).…”

mTORC1 signaling in energy balance and metabolic disease

“…The latter is among the pathways known to mediate the appetite-suppressing actions of insulin and leptin in the hypothalamus. 25,26 In the presence of insulin, phosphorylation of Akt leads to inhibition of the tuberous sclerosis protein 2 (TSC2), which downregulates mTORC1 by inhibiting the GTPase Rheb (Ras homolog enriched in the brain). This therefore leads to mTORC1 activation.…”