Evidence Suggesting A Potential Role Of The Phosphodiesterase-3B Pathway In Hypothalamic Action Of Insulin On Feeding

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 649-675-Central Regulation of Appetite & Feeding/GI Regulatory Peptides
Bench to Bedside
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-657
Abhiram Sahu*, Prashanth Anamthathmakula and Maitrayee Sahu
University of Pittsburgh School of Medicine, Pittsburgh, PA
Insulin signaling in the hypothalamus plays a critical role in regulation of normal energy homeostasis, but the intracellular signaling mechanisms underlying this energy regulation are incompletely understood. Insulin stimulates phosphatidylinositol-3 kinase activity in the hypothalamus and PI3K inhibitor reverses anorectic effect of this hormone, suggesting the importance of this pathway in controlling food intake. In peripheral tissues, however, insulin signaling involves activation of phosphodiesterase-3B (PDE3B), and we have recently shown that insulin stimulates PDE3B activity in the hypothalamus (1). It is still unknown if PDE3B plays any role in mediating hypothalamic action of insulin on feeding and body weight regulation. We therefore tested the hypothesis that PDE3B mediates insulin action in the hypothalamus. To this end, in the 1st experiment, we examined the effects of cilostamide, a PDE3 inhibitor, on anorectic and body weight reducing effects of insulin.  Adult male mice with indwelling lateral cerebroventricular (LCV) cannula were injected icv with cilostamide (10 µg/µl) or DMSO (vehicle) 5 hours before the lights off and food was withdrawn. Forty min later, mice were injected icv with insulin (4.4 mU/2µl) or saline. Food (rodent chow) was given at 6 PM and food intake was measured at 12 and 24 hr; and body wt was measured at 24 hr post-injection. We observed that insulin significantly decreased food intake at 12  (p < 0.01) and 24 hr (p < 0.01) and body weight at 24 hr (p < 0.05), and cilostamide reversed these effects of insulin, suggesting a potential role of the PDE3B pathway in mediating insulin action in the hypothalamus in regulating energy homeostasis. Because insulin signaling in POMC neurons plays important role in energy homeostasis, and PDE3B is also expressed in these neurons (2), in the 2nd experiment, we examined if cilostamide reversed the insulin-induced increase in POMC gene expression in the medial basal hypothalamus (MBH). Mice with indwelling LCV cannula fasted for 24 hours were injected icv with cilostamide (10 µg/µl) or DMSO followed 40 min later with icv insulin (4.4 mU/2µl) or saline injection. Two hours later, mice were sacrificed and the MBH were processed for proopiomelanocortin (POMC) gene expression by qPCR. Results showed that insulin significantly increased POMC mRNA levels  (p < 0.01) as expected, however, prior treatment with cilostamide reversed this effect, suggesting a role of PDE3B in mediating insulin action in POMC neurons. These results altogether show for the first time that PDE3B mediates hypothalamic action of insulin on feeding, and this action is transduced, at least partly, via the PDE3B pathway of insulin signaling in POMC neurons.

(1) Sahu A et al. Program No.389.24. 2012 Neuroscience Meeting Planner, New Orleans, Society for Neuroscience. 2012. Online.  (2) Sahu M et al. Neuroscience Letters 2011; 505:93-97.

Nothing to Disclose: AS, PA, MS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Grant DK78068 awarded to AS