AgRP Deficient Female but not Male Mice have Elevated Hypothalamic Mitochondrial Oxidative Capacity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 685-694-Mechanisms of Obesity
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-689
Brian A Irving*, Steve Roesch, Crystal Kane, Amanda Styer and George Argyropoulos
Geisinger Health System, Danville, PA
The central orexigenic agouti-related protein (AgRP) increases food intake when ubiquitously over expressed.  Previous reports using AgRP deficient (Agrp-KO) mice from mixed genetic backgrounds have demonstrated either 1) no phenotype, or 2) increased body weight, or 3) increased longevity.  Here, we show that Female, but not male (FVB) AgRP-KO mice have elevated food intake.  Moreover, the female (FVB) AgRP-KO mice tend to be heavier than their wild type (WT) littermates.  We tested the hypothesis that differences in mitochondrial respiration could contribute to the propensity of the female (FVB) AgRP-KO mice to eat more and gain more weight compared to their WT littermates.  High-resolution respirometry was utilized to perform a multiple substrate-inhibitor titration (SUIT) protocol designed to assess mitochondrial oxidative respiratory states in permeabilized hypothalamic, liver, skeletal muscle, and white adipose tissue acquired from ~120 day old male and female AgRP-KO and their WT littermates.  In the hypothalamus, the female AgRP-KO mice had higher non-phosphorylating (LEAK) respiration (15.2±2.5 vs. 7.2±0.7 pmol/s/mg, p=0.023), oxidative phosphorylation (OXPHOS) capacity (61.0±3.7 vs. 47.7±2.5 pmol/s/mg, p=0.015), and higher electron transfer system (ETS) capacity (66.3±4.5 vs. 53.3±2.9 pmol/s/mg, p=0.040) than their WT littermates.  No significant differences between male AgRP-KO and their WT littermates were observed for hypothalamic LEAK respiration (11.6±1.4 vs. 9.6±1.1 pmol/s/mg, p>0.1), OXPHOS capacity (50.2±2.6 vs. 46.3±5.5 pmol/s/mg, p>0.1), or ETS capacity (52.9±3.8 vs. 52.2±4.3 pmol/s/mg, p>0.1).  There were no significant differences between groups for the O2 fluxes in the liver, white adipose tissue, or gastrocnemius muscle in neither the males nor females.  In conclusion, AgRP deficiency in female mice results in elevations in hypothalamic LEAK respiration, OXPHOX capacity, and ETS capacity, which may contribute to their increased food intake and body weight.

Nothing to Disclose: BAI, SR, CK, AS, GA

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