Oral Presentation Australian & New Zealand Obesity Society 2014 Annual Scientific Meeting

Disruption of glucocorticoid signaling in osteoblasts prevents age-associated metabolic dysfunction in mice (#76)

Holger Henneicke 1 , Jingbao Li 1 2 , Sylvia J. Gasparini 1 , Markus J. Seibel 1 3 , Hong Zhou 1
  1. Bone Research Program, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia
  2. Key Laboratory for Space & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
  3. Department of Endocrinology and Metabolism, Concord Hospital, University of Sydney, Sydney, NSW, Australia

The physiological ageing process is associated with changes in body composition and metabolism, including central obesity, diabetes and osteoporosis. The osteoblast has recently been identified as a mediator of GC-induced metabolic dysfunction in mice (1). We therefore hypothesised that a mechanistic link exists between increased GC signaling in the osteoblast and changes in body composition and fuel metabolism during ageing.

To test this hypothesis, we investigated the ageing phenotype of transgenic (tg) mice in which glucocorticoid signaling had been selectively disrupted in osteoblasts/osteocytes via targeted overexpression of the glucocorticoid-inactivating enzyme, 11ßHSD2. Body weight and composition, insulin sensitivity and glucose tolerance, serum corticosterone (CS) and osteocalcin levels as well as hepatic gene expression patterns were assessed in female 11ßHSD2-tg mice and litter-matched wild-type (WT) controls at 2 and 18 months of age.

From 2 to 18 months of age, female WT mice gained more in body weight (WT: +32g vs tg: +16g, p<0.01) and overall fat mass (WT: +20.7g vs tg: +6.3g, p<0.01) than their tg littermates. Eighteen-months-old WT mice exhibited reduced insulin sensitivity and hepatosteatosis, while insulin responsiveness and hepatic lipid deposition remained normal in their age-matched tg littermates. Hepatic mRNA expression of lipogenic and gluconeogenic genes was higher in aged WT compared to aged tg mice (acetyl-coA-carboxylase, WT: 12.8 vs tg: 5.6-fold increase on respective young controls, p=0.051; glucose-6-phosphatase, WT: 8.1 vs tg: 3.3-fold increase on respective young controls, p=0.09). Serum CS concentrations were similar in 18-month-old WT and tg mice and ~3-fold higher than in 2-month-old mice (p<0.05). Serum osteocalcin concentrations declined during ageing in both genotypes. Interestingly, osteocalcin remained significantly higher in tg mice at young but not at old age (p<0.05 & p=0.587).

Conclusion: In mice glucocorticoid signaling in osteoblasts is critically involved in the pathogenesis of age-related changes in glucose handling and body composition.

  1. Brennan-Speranza & Henneicke et al., JCI. 2012;122(11):4172-89