Hypothalamic POMC neurons regulate intestinal glucose absorption via a gut-brain circuit

Hypothalamic proopiomelanocortin (POMC)-producing neurons are essential for maintaining energy balance and glucose homeostasis. We show that cAMP-dependent protein kinase A (PKA) signaling in these neurons is activated postprandially and upon the administration of glucagon-like peptide-1-based antiobesity/antidiabetic agents. To investigate the metabolic regulatory role of PKA signaling in hypothalamic POMC neurons, we generated mice with POMC-specific constitutive PKA activation by depleting the PKA regulatory subunit Prkar1a. These mice developed obesity due to PKA activation in pituitary corticotrophs and hypercortisolism. Despite increased insulin resistance, these animals exhibited a marked improvement in glucose tolerance, attributable to reduced intestinal glucose absorption and increased fecal glucose excretion. Mechanistically, PKA activation in hypothalamic POMC neurons stimulated upper gut innervating-vagal motor neurons, leading to a suppression of sodium/glucose cotransporter-1 (SGLT1)-dependent intestinal glucose absorption. Our findings indicate that the POMC PKA signaling-vagal-gut SGLT1 axis may be a potential target for antidiabetic treatment in individuals with insulin resistance.