FP30-6 Deletion of Protein Kinase C lambda in POMC neurons predisposes to diet-induced obesity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP30-Central Regulation of Appetite & Feeding
Basic
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:10 AM
Room 304 (Moscone Center)

Poster Board MON-650
Mauricio D Dorfman*, Vincent Damian, Miles Matsen, Michael W Schwartz and Joshua P Thaler
University of Washington, Seattle, WA
Protein kinase C ζ and λ are the two members of the atypical subfamily of PKC isoforms (aPKC) that differ from classical PKCs in their calcium and diacylglycerol-independent regulation. We previously reported that aPKC is expressed in the mediobasal hypothalamus (MBH) (1), a key site for hypothalamic regulation of energy balance, and can be activated by the adiposity negative feedback signals insulin and leptin. Since these hormones act in the MBH to reduce food intake, we predicted that CNS inhibition of aPKC would increase food intake. To test this hypothesis, we administered a specific aPKC inhibitor (myristoylated aPKC pseudosubstrate inhibitor; aPKC-i) intracerebroventricularly in adult male Wistar rats (n=8/group). As expected, this intervention increased 4 h and 8 h food intake by 71% and 25%, respectively. To investigate whether neuronal aPKC activity plays a physiological role to protect against diet-induced obesity (DIO), we used osmotic minipumps to continuously infuse aPKC-i into the lateral ventricle of adult male Wistar rats (n=6/group) for 14 d during the initiation of high-fat diet (HFD) feeding. Our finding that central inhibition of aPKC increased both weight gain and food intake on a HFD (by 22% and 12.5%, respectively) suggests a role for the enzyme within energy balance neurocircuits to protect against DIO. Based on these results and the known role of pro-opiomelanocortin (POMC) neurons to limit food intake and protect against DIO, we generated a conditional knockout mouse in which the gene encoding Pkc-λ is deleted specifically in POMC neurons (Pomc;Pkc-λ-/-) using Cre-loxP technology. Eight groups of mice (n=10-11/group) were studied based on genotype (wild-type (WT) or Pomc;Pkc-λ-/- (KO)), sex (female (F) or male (M)) and diet (chow or HFD) for 12 wk. While F-KO mice were indistinguishable from WT controls, weight gain and food intake on the HFD were both increased (by 15% and 8%, respectively) in M-KO mice vs. M-WT controls. Our findings strongly suggest that the ability of POMC neurons to protect against DIO is dependent on aPKC activity.

(1) Thaler JP et al., Endocrinology 2009; 150(12):5362-5372.

Nothing to Disclose: MDD, VD, MM, MWS, JPT

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

Sources of Research Support: R01 NIH Grants DK052989 and DK090320 (to M.W.S.); Pilot Feasibility Grant DK035816 by Nutrition and Obesity Research Center (to J.P.T.); K08 Grant DK088872 to (J.P.T.)
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