Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity
Kristen P. Tolson, … , Jeremy T. Smith, Alexander S. Kauffman
Kristen P. Tolson, … , Jeremy T. Smith, Alexander S. Kauffman
Published June 17, 2014
Citation Information: J Clin Invest. 2014;124(7):3075-3079. https://doi.org/10.1172/JCI71075.
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Brief Report

Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity

Abstract

The neuropeptide kisspeptin regulates reproduction by stimulating gonadotropin-releasing hormone (GnRH) neurons via the kisspeptin receptor KISS1R. In addition to GnRH neurons, KISS1R is expressed in other brain areas and peripheral tissues, which suggests that kisspeptin has additional functions beyond reproduction. Here, we studied the energetic and metabolic phenotype in mice lacking kisspeptin signaling (Kiss1r KO mice). Compared with WT littermates, adult Kiss1r KO females displayed dramatically higher BW, leptin levels, and adiposity, along with strikingly impaired glucose tolerance. Conversely, male Kiss1r KO mice had normal BW and glucose regulation. Surprisingly, despite their obesity, Kiss1r KO females ate less than WT females; however, Kiss1r KO females displayed markedly reduced locomotor activity, respiratory rate, and energy expenditure, which were not due to impaired thyroid hormone secretion. The BW and metabolic phenotype in Kiss1r KO females was not solely reflective of absent gonadal estrogen, as chronically ovariectomized Kiss1r KO females developed obesity, hyperleptinemia, reduced metabolism, and glucose intolerance compared with ovariectomized WT females. Our findings demonstrate that in addition to reproduction, kisspeptin signaling influences BW, energy expenditure, and glucose homeostasis in a sexually dimorphic and partially sex steroid–independent manner; therefore, alterations in kisspeptin signaling might contribute, directly or indirectly, to some facets of human obesity, diabetes, or metabolic dysfunction.

Authors

Kristen P. Tolson, Christian Garcia, Stephanie Yen, Stephanie Simonds, Aneta Stefanidis, Alison Lawrence, Jeremy T. Smith, Alexander S. Kauffman

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Figure 3

Effects of GDX/OVX and diet on BW and metabolic parameters in Kiss1r KO mice.

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Effects of GDX/OVX and diet on BW and metabolic parameters in Kiss1r KO ...
Standard chow–fed Kiss1r KO and WT and Het control females were OVX before puberty (2 weeks old; A) or just after puberty (5 weeks old; B) and weighed weekly. (C) Percent BW of week-21 Kiss1r KO and control females OVX at week 2 or week 5, relative to gonad-intact controls (assigned as 100%). (D) Fat mass in adult Kiss1r KO and WT females OVX at 2 weeks. (E) BW of gonad-intact Gnrhhpg and control female mice. (F) Percent BW of week-18 gonad-intact Gnrhhpg and Kiss1r KO females relative to gonad-intact controls from the same strains. (G and H) BW of female and male Kiss1r KO and WT mice OVX or GDX in young adulthood and challenged with HFD. Fat mass (I), GTT (J), and metabolic measures (K) of HFD-fed OVX Kiss1r KO and WT females. †P < 0.05, OVX Kiss1r KO vs. intact control; §P < 0.05, OVX Kiss1r KO vs. OVX control; #P < 0.05, OVX control vs. intact control; *P < 0.05 as indicated.