Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice

Holger Henneicke; Sarah Kim; Michael M. Swarbrick; Jingbao Li; Sylvia J. Gasparini; Joanne Thai; Daphne Foong; Lauryn L. Cavanagh; Colette Fong-Yee; Elisabeth Karsten; Ruby C.Y. Lin; Mark S. Cooper; Hong Zhou; Markus J. Seibel

Molecular Metabolism (Dec 2020)

Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice

Holger Henneicke,
Sarah Kim,
Michael M. Swarbrick,
Jingbao Li,
Sylvia J. Gasparini,
Joanne Thai,
Daphne Foong,
Lauryn L. Cavanagh,
Colette Fong-Yee,
Elisabeth Karsten,
Ruby C.Y. Lin,
Mark S. Cooper,
Hong Zhou,
Markus J. Seibel

Affiliations

Holger Henneicke: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Germany; Department of Medicine III, Technische Universität Dresden, Germany; Center for Healthy Aging, Technische Universität Dresden, Germany
Sarah Kim: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia
Michael M. Swarbrick: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia
Jingbao Li: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Key Laboratory for Space Bioscience & Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, China
Sylvia J. Gasparini: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia
Joanne Thai: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia
Daphne Foong: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia
Lauryn L. Cavanagh: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia
Colette Fong-Yee: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia
Elisabeth Karsten: Kolling Institute of Medical Research, The University of Sydney, Australia
Ruby C.Y. Lin: Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, The University of Sydney, Australia; School of Medical Sciences, University of New South Wales Sydney, Australia
Mark S. Cooper: Concord Clinical School, The University of Sydney, Australia
Hong Zhou: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia; Corresponding author. Bone Research Program, ANZAC Research Institute, The University of Sydney, Hospital Road, Concord, NSW 2139, Australia. Fax: +61 2 9767 9101.
Markus J. Seibel: Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia

Journal volume & issue: Vol. 42
p. 101098

Abstract

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Objective: Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging. Methods: Mice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus STAT3 phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured. Results: As they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2OB/OCY-tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic STAT3, from 6 months of age onwards. In contrast, HSD2OB/OCY-tg mice remained leptin-sensitive throughout the study. Compared to HSD2OB/OCY-tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2OB/OCY-tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2OB/OCY-tg mice, compared to wild-type mice. Conclusions: Skeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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