276-LB: Constitutive Activation of PKA Signaling in POMC-Expressing Cells Improves Systemic Glucose Metabolism

Abstract

Constitutive Proopiomelanocortin (POMC)-expressing cells are mainly found in the hypothalamic arcuate nucleus, brainstem solitary tract nucleus, and pituitary gland. The cAMP-dependent protein kinase A (PKA) critically transduces signaling pathways of many important hormones and neurotransmitters including glucagon, GLP-1, α-MSH, dopamine and catecholamine. We generated the mice deleting PKA regulatory subunit R1A (Prkar1a) in POMC-expressing cells to induce constitutive activation of PKA signaling in POMC cells. These mice exhibited interesting phenotypes similar to human Cushing's syndrome; thin skin, hair loss, increased fat mass but reduced muscle and bone mass, female infertility, retarded linear growth, hump and insulin resistance. Moreover, they had increased corticosterone levels both in urine and plasma along with adrenal cortical hypertrophy. Interestingly, despite severe insulin resistance and obesity, plasma glucose concentrations were significantly lower in both fasting and post-glucose loading conditions. These mice showed enhanced insulin-independent glucose disposal. FDG-PET scanning and 2DG uptake tests revealed increased glucose uptake in the brain and the kidney. Normalization of corticosteroid levels by bilateral adrenalectomy and corticosteroid replacement could not normalize blood glucose. Collectively, our hypothesis is that abnormal activation of PKA signaling in pituitary POMC cells causes human Cushing’s syndrome-like phenotype whereas unusual activation of PKA signaling in hypothalamic POMC neurons enhances glucose disposal in the brain and the kidney. Disclosure J. Choi: None. S. Min: None. G. Kang: None. J. Kim: None. M. Kim: None. Funding National Research Foundation of Korea