FP39-6 Impaired kisspeptin signaling induces an obese and diabetic phenotype in adult mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP39-Pituitary
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:10 AM
Room 133 (Moscone Center)

Poster Board MON-116
Kristen P Tolson*1, Stephanie C Yen2, Stephanie Simmonds3, Aneta Stefanidis3, Jeremy Troy Smith4 and Alexander S Kauffman2
1University of California, San Diego, La Jolla, CA, 2University of California San Diego, La Jolla, CA, 3Monash University, Melbourne, Australia, 4The University of Western Australia, Perth, Australia
Kisspeptin potently regulates reproduction by signaling directly to GnRH neurons through its receptor, KISS1R, formerly known as G-protein coupled receptor 54 (GPR54). However, in addition to being expressed in GnRH cells, KISS1R is also expressed in many other brain areas, as well as in the periphery, suggesting that kisspeptin may have additional functions outside of governing reproductive status. Interestingly, Kiss1, the gene encoding kisspeptin, is expressed in the arcuate nucleus, and kisspeptin can directly excite anorexigenic POMC neurons and indirectly inhibit orexigenic NPY neurons. Thus, kisspeptin may have a role in metabolic status and energy balance, though this possibility has not been closely examined. Although a previous study of young Kiss1r knockout (KO) and wild type (WT) mice found no genotype differences in body weight, our preliminary observations indicated that Kiss1r KO females displayed later onset obesity. Therefore we performed an intensive examination of the Kiss1r KO metabolic phenotype. We found no major difference in male KO body weights or food intake compared to WT littermates. In stark contrast, female KO mice weighed the same as WT littermates until 8 weeks of age when they began displaying substantially larger weight gain. Adult KO females also had significantly higher serum leptin levels and over double the amount of fat mass as WTs, while displaying a small, but significant, decrease in lean mass. KO males do not display an overall body weight difference, but they too had less lean mass and more fat mass than WT males. KO females also had strikingly impaired glucose tolerance and higher basal glucose levels, but only secondary to obesity. Surprisingly, despite their increased body weight and fat mass, adult KO females ate less than WT females. However, KO females displayed significantly less daily locomotor activity and significantly lower respiration rates. Finally, we examined many of the same parameters in KO mice that had been gonadectomized (GDX) to normalize gonadal sex steroid levels to determine if metabolic changes in the absence of kisspeptin-Kiss1r signaling were due to low levels of sex steroids. KO females still displayed changes in body weight and composition on both chow and high fat diets. Thus, our novel data demonstrate that, in addition to regulating reproduction, kisspeptin signaling may also be an important regulator of body weight and glucose homeostasis.

Nothing to Disclose: KPT, SCY, SS, AS, JTS, ASK

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

Sources of Research Support: This research was supported by NIH grant T32 HD007203-29 (KPT), NSF grant IOS-1025893 and NIH grant R01 HD065856 (ASK), as well as NHMRC, 606538 ARC, FT0990986 and DP120100521 (JTS).
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