Unsilencing of native LepRs in hypothalamic SF1 neurons does not rescue obese phenotype in LepR-deficient mice

Seraina S. Senn, Christelle Le Foll, Lynda Whiting, Erika Tarasco, Sonya Duffy, Thomas A. Lutz, Christina Neuner Boyle

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8 Citations (Scopus)

Abstract

Leptin receptor (LepR) signaling in neurons of the ventromedial nucleus of the hypothalamus (VMH), specifically those expressing steroidogenic factor-1 (SF1), have been proposed to play a key role in controlling energy balance. By crossing LepR-silenced (LepRloxTB) mice with those expressing SF1-Cre, we unsilenced native LepR specifically in the VMH and tested whether SF1 neurons in the VMH are critical mediators of leptin's effect on energy homeostasis. LepRloxTB × SF1-Cre [knockout (KO)/Tg+] mice were metabolically phenotyped and compared with littermate controls that either expressed or were deficient in LepRs. Leptin-induced phosphorylated STAT3 was present in the VMH of KO/Tg+ mice and absent in other hypothalamic nuclei. VMH leptin signaling did not ameliorate obesity resulting from LepR deficiency in chow-fed mice. There was no change in food intake or energy expenditure when comparing complete LepR-null mice with KO/Tg+ mice, nor did KO/Tg+ mice show improved glucose tolerance. The presence of functional LepRs in the VMH mildly enhanced sensitivity to the pancreatic hormone amylin. When maintained on a high-fat diet (HFD), there was no reduction in diet-induced obesity in KO/Tg+ mice, but KO/Tg+ mice had improved glucose tolerance after 7 wk on an HFD compared with LepR-null mice. We conclude that LepR signaling in the VMH alone is not sufficient to correct metabolic dysfunction observed in LepR-null mice.

Original languageEnglish
Pages (from-to)R451-R460
Number of pages10
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume317
Issue number3
DOIs
Publication statusPublished - 4 Sep 2019
Externally publishedYes

Keywords

  • amylin
  • energy expenditure
  • high-fat diet
  • insulin
  • meal pattern
  • oral glucose tolerance test

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