Hypothalamic WNT Signalling Is Impaired During Obesity and Reinstated by Leptin Treatment in Male Mice

Author:

Benzler Jonas1,Andrews Zane B.2,Pracht Corinna1,Stöhr Sigrid1,Shepherd Peter R.3,Grattan David R4,Tups Alexander1

Affiliation:

1. Department of Animal Physiology (J.B., C.P., S.S., A.T.), Faculty of Biology, Philipps University Marburg, 35032 Marburg, Germany

2. Department of Physiology (Z.B.A.), Monash University, Melbourne, Victoria 3800, Australia

3. Maurice Wilkins Centre for Molecular Biodiscovery and Department of Molecular Medicine and Pathology (P.R.S.), University of Auckland, Auckland, New Zealand

4. Centre for Neuroendocrinology and Department of Anatomy (D.R.G.), University of Otago, Dunedin 9054, New Zealand

Abstract

The WNT pathway has been well characterized in embryogenesis and tumorigenesis. In humans, specific polymorphisms in the T cell-specific transcription factor 7 and the WNT coreceptor, low-density lipoprotein receptor-related protein-6 (LRP-6), both prominent components of this pathway, correlate with a higher incidence of type 2 diabetes, suggesting that the WNT pathway might be involved in the control of adult glucose homeostasis. We previously demonstrated that glycogen-synthase-kinase-3β (GSK-3β), the key enzyme of the WNT pathway, is increased in the hypothalamus during obesity and exacerbates high-fat diet-induced weight gain as well as glucose intolerance. These data suggest that WNT action in the hypothalamus might be required for normal glucose homeostasis. Here we characterized whether WNT signaling in general is altered in the hypothalamus of adult obese mice relative to controls. First we identified expression of multiple components of this pathway in the murine arcuate nucleus by in situ hybridization. In this region mRNA of ligands and target genes of the WNT pathway were down-regulated in obese and glucose-intolerant leptin-deficient mice. Similarly, the number of cells immunoreactive for the phosphorylated (active) form of the WNT-coreceptor LRP-6 was also decreased in leptin-deficient mice. Leptin treatment normalized expression of the WNT-target genes Axin-2 and Cylin-D1 and increased the number of phospho-LRP-6-immunoreactive cells reaching levels of lean controls. Leptin also increased the levels of phosphorylated (inactive) GSK-3β in the arcuate nucleus, and this effect was colocalized to neuropeptide Y neurons, suggesting that inactivation of GSK-3β may contribute to the neuroendocrine control of energy homeostasis. Taken together our findings identify hypothalamic WNT signaling as an important novel pathway that integrates peripheral information of the body's energy status encoded by leptin.

Publisher

The Endocrine Society

Subject

Endocrinology

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