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

doi:10.1016/j.molmet.2020.101098

Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice

Mol Metab. 2020 Dec:42:101098. doi: 10.1016/j.molmet.2020.101098. Epub 2020 Oct 10.

Authors

Affiliations

¹ 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. Electronic address: holger.henneicke@tu-dresden.de.
² Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia. Electronic address: sarah.kim1@sydney.edu.au.
³ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia. Electronic address: michael.swarbrick@sydney.edu.au.
⁴ 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. Electronic address: lijingbao@nwpu.edu.cn.
⁵ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia. Electronic address: sylvia.gasparini@tu-dresden.de.
⁶ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia. Electronic address: joanne.thai@sydney.edu.au.
⁷ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia. Electronic address: daphne.foong@sydney.edu.au.
⁸ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia. Electronic address: lauryn.cavanagh@sydney.edu.au.
⁹ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia. Electronic address: colette.fong-yee@sydney.edu.au.
¹⁰ Kolling Institute of Medical Research, The University of Sydney, Australia. Electronic address: elisabeth@sanguibio.com.
¹¹ 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. Electronic address: ruby.lin@sydney.edu.au.
¹² Concord Clinical School, The University of Sydney, Australia. Electronic address: mark.cooper@sydney.edu.au.
¹³ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia. Electronic address: h.zhou@sydney.edu.au.
¹⁴ Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia. Electronic address: markus.seibel@sydney.edu.au.

Abstract

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 (HSD2^OB/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, HSD2^OB/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, HSD2^OB/OCY-tg mice remained leptin-sensitive throughout the study. Compared to HSD2^OB/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 HSD2^OB/OCY-tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2^OB/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.

Keywords: Aging; Appetite; Glucocorticoid; Leptin; Obesity; Osteoblast; Osteocyte.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism
Age Factors
Aging / metabolism*
Animals
Arcuate Nucleus of Hypothalamus / metabolism
Body Composition
Body Weight / physiology
Bone and Bones / metabolism
Brain / metabolism
Female
Glucocorticoids / metabolism*
Glucose / metabolism
Hypothalamus / metabolism
Insulin / metabolism
Insulin Resistance / physiology
Leptin / metabolism*
Mice
Mice, Inbred C57BL
Mice, Obese
Mice, Transgenic
Obesity / metabolism
Obesity / physiopathology
Signal Transduction / drug effects
Thermogenesis

Substances

Glucocorticoids
Insulin
Leptin
Glucose