Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice

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

doi:10.1016/j.molmet.2020.101098

Cited by 11 publications

(11 citation statements)

References 50 publications

(82 reference statements)

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“…Unlike WT mice, transgenic HSD2 OB/OCY -tg mice were protected against ageing-related declines in leptin sensitivity: as they aged, HSD2 OB/OCY -tg mice maintained their leptin-mediated suppression of food intake and stimulation of adipose tissue sympathetic outflow, in contrast to their WT littermates (121). While the mechanisms linking osteoblastic glucocorticoid signalling with the CNS are not well understood, they do not appear to involve changes in the osteoblast-derived hormones osteocalcin or lipocalin-2 (121). Similarly, deleting the GR from osteoprogenitor cells also reduces body weight in mice by ~10% (122).…”

Section: Chronic Glucocorticoids and Bonementioning

confidence: 95%

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

Swarbrick

Zhou

Seibel

2021

European Journal of Endocrinology

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Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores, but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is therefore critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (11β-HSD1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive 11β-HSD1 activity, amplifying local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and aging-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated the mechanisms by which glucocorticoids exert their metabolic effects; and have guided us towards more targeted future treatments for metabolic diseases.

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Section: Chronic Glucocorticoids and Bonementioning

confidence: 95%

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

Swarbrick

Zhou

Seibel

2021

European Journal of Endocrinology

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“…The lack of an obvious skeletal-derived endocrine effect has also been reported in many other recent studies. 24,42,[47][48][49] Instead, our results implicate Wnt signaling as a potential molecular link between increased skeletal glucose uptake and enhanced bone formation in HFD-fed HSD2 OB/OCY -tg mice. Wnt signaling is a major driver of bone formation, 27 determining nearly all aspects of osteoblast function, 50 and is inhibited by glucocorticoids.…”

Section: Hfd Feeding Increased Local Glucocorticoid Signaling In Bonementioning

confidence: 55%

“… 22 , 23 Skeletal expression of 11β-HSD2 protein was confirmed by RT-PCR and immunohistochemistry. 24 From 7 weeks of age, mice were fed either regular chow or HFD (43% of calories from fat) for 8 and 18 weeks.…”

Section: Resultsmentioning

confidence: 99%

“…These effects were consistent with our previous studies. 19 , 24 , 26 Female HSD2 OB/OCY -tg mice fed HFD displayed a similar bone phenotype but were not studied further, as they did not develop insulin resistance (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…The lack of an obvious skeletal-derived endocrine effect has also been reported in many other recent studies. 24 , 42 , 47 – 49 …”

Section: Discussionmentioning

confidence: 99%

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Osteoblastic glucocorticoid signaling exacerbates high-fat-diet- induced bone loss and obesity

et al. 2021

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Chronic high-fat diet (HFD) consumption not only promotes obesity and insulin resistance, but also causes bone loss through mechanisms that are not well understood. Here, we fed wild-type CD-1 mice either chow or a HFD (43% of energy from fat) for 18 weeks; HFD-fed mice exhibited decreased trabecular volume (−28%) and cortical thickness (−14%) compared to chow-fed mice. In HFD-fed mice, bone loss was due to reduced bone formation and mineral apposition, without obvious effects on bone resorption. HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network (LCN). In mice fed HFD, skeletal glucocorticoid signaling was activated relative to chow-fed mice, independent of serum corticosterone concentrations. We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss, using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice). In HSD2OB/OCY-tg mice, bone formation and mineral apposition rates were not suppressed by HFD, and bone loss was significantly attenuated. Interestingly, in HSD2OB/OCY-tg mice fed HFD, both Wnt signaling (less sclerostin induction, increased β-catenin expression) and glucose uptake were significantly increased, relative to diet- and genotype-matched controls. The osteocyte LCN remained intact in HFD-fed HSD2OB/OCY-tg mice. When fed a HFD, HSD2OB/OCY-tg mice also increased their energy expenditure and were protected against obesity, insulin resistance, and dyslipidemia. Therefore, glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice. Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone, which influences the whole-body metabolic response to HFD.

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The Glucocorticoid Receptor in Osterix-Expressing Cells Regulates Bone Mass, Bone Marrow Adipose Tissue, and Systemic Metabolism in Female Mice During Aging

Pierce

Sharma

Roberts

et al. 2020

Journal of Bone and Mineral Research

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Hallmarks of aging‐associated osteoporosis include bone loss, bone marrow adipose tissue (BMAT) expansion, and impaired osteoblast function. Endogenous glucocorticoid levels increase with age, and elevated glucocorticoid signaling, associated with chronic stress and dysregulated metabolism, can have a deleterious effect on bone mass. Canonical glucocorticoid signaling through the glucocorticoid receptor (GR) was recently investigated as a mediator of osteoporosis during the stress of chronic caloric restriction. To address the role of the GR in an aging‐associated osteoporotic phenotype, the current study utilized female GR conditional knockout (GR‐CKO; GRfl/fl:Osx‐Cre+) mice and control littermates on the C57BL/6 background aged to 21 months and studied in comparison to young (3‐ and 6‐month‐old) mice. GR deficiency in Osx‐expressing cells led to low bone mass and BMAT accumulation that persisted with aging. Surprisingly, however, GR‐CKO mice also exhibited alterations in muscle mass (reduced % lean mass and soleus fiber size), accompanied by reduced voluntary physical activity, and also exhibited higher whole‐body metabolic rate and elevated blood pressure. Moreover, increased lipid storage was observed in GR‐CKO osteoblastic cultures in a glucocorticoid‐dependent fashion despite genetic deletion of the GR, and could be reversed via pharmacological inhibition of the mineralocorticoid receptor (MR). These findings provide evidence of a role for the GR (and possibly the MR) in facilitating healthy bone maintenance with aging in females. The effects of GR‐deficient bone on whole‐body physiology also demonstrate the importance of bone as an endocrine organ and suggest evidence for compensatory mechanisms that facilitate glucocorticoid signaling in the absence of osteoblastic GR function; these represent new avenues of research that may improve understanding of glucocorticoid signaling in bone toward the development of novel osteogenic agents. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice

Cited by 11 publications

References 50 publications

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

Osteoblastic glucocorticoid signaling exacerbates high-fat-diet- induced bone loss and obesity

The Glucocorticoid Receptor in Osterix-Expressing Cells Regulates Bone Mass, Bone Marrow Adipose Tissue, and Systemic Metabolism in Female Mice During Aging

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