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Unsilencing of native leptin receptors (LepR) in hypothalamic SF1 neurons does not rescue obese phenotype in LepR-deficient mice


Senn, Seraina S; Le Foll, Christelle; Whiting, Lynda; Tarasco, Erika; Duffy, Sonya; Lutz, Thomas A; Boyle, Christina Neuner (2019). Unsilencing of native leptin receptors (LepR) in hypothalamic SF1 neurons does not rescue obese phenotype in LepR-deficient mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 317(3):R451-R460.

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 (LepR) mice to 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. LepR x SF1-Cre (KO/Tg+) mice were metabolically phenotyped and compared to littermate controls that either expressed or were deficient in LepR. Leptin-induced pSTAT3 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 to KO/Tg+ mice, nor did KO/Tg+ show improved glucose tolerance. The presence of functional LepR in the VMH mildly enhanced sensitivity to the pancreatic hormone amylin. When maintained on 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 weeks on HFD compared to LepR-null mice. We conclude that LepR signaling in the VMH alone is not sufficient to correct metabolic dysfunction observed in LepR-null mice.

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 (LepR) mice to 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. LepR x SF1-Cre (KO/Tg+) mice were metabolically phenotyped and compared to littermate controls that either expressed or were deficient in LepR. Leptin-induced pSTAT3 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 to KO/Tg+ mice, nor did KO/Tg+ show improved glucose tolerance. The presence of functional LepR in the VMH mildly enhanced sensitivity to the pancreatic hormone amylin. When maintained on 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 weeks on HFD compared to LepR-null mice. We conclude that LepR signaling in the VMH alone is not sufficient to correct metabolic dysfunction observed in LepR-null mice.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:amylin; energy expenditure; high fat diet; insulin; meal pattern
Language:English
Date:1 September 2019
Deposited On:31 Jul 2019 11:32
Last Modified:01 Oct 2019 11:38
Publisher:American Physiological Society
ISSN:0363-6119
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1152/ajpregu.00111.2019
PubMed ID:31314542
Project Information:
  • : FunderSNSF
  • : Grant ID31003A-175458
  • : Project Title

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Language: English
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Embargo till: 2020-07-17