Targeted Disruption of Glucocorticoid Signaling in Osteoblasts and Osteocytes Protects from Diet-Induced Obesity, Insulin Resistance and Bone Loss

Presentation Number: OR02-3
Date of Presentation: April 4th, 2017

Sarah Kim*1, Holger Henneicke2, Sylvia J Gasparini1, Lee Thai1, Markus J Seibel3 and Hong Zhou1
1ANZAC Research Institute, The University of Sydney, Sydney, Australia, 2DFG-Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany, 3Concord Hospital & The University of Sydney, Sydney, Australia

Abstract

Overconsumption of energy-dense diets has become a major public health challenge due its causal association with obesity, diabetes and poor skeletal health. However, most animal studies that examine diet-induced obesity and diabetes have focused solely on very high-energy high-fat feeding and thus, we aimed to determine whether these adverse health outcomes are due to the high-energy density or high-fat component of diets. Further, we have previously shown that disruption of glucocorticoid signaling in bone protects mice from the adverse metabolic side effects of exogenous glucocorticoids hence, we also aimed to investigate whether abrogating glucocorticoid signaling in bone can protect from diet-induced metabolic disturbances.

To this end, we utilized a transgenic (tg) mouse model in which glucocorticoid signaling has been selectively disrupted in osteoblasts and osteocytes via targeted overexpression of the glucocorticoid-inactivating enzyme, 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2. To compare the effects of high-energy versus high-fat, two high-energy diets (both 16.3 kJ/g) were designed: standard-fat (SFDhigh; 14% total energy as fat) and high-fat (HFDhigh; 43% total energy as fat). A standard chow was used as control (13.8 kJ/g, 14% total energy as fat). Seven-week-old male tg mice and their wild type (WT) littermates (n=11-15/group) were fed ad libitumfor 18 weeks. At endpoint, body composition, glucose handling and bone mass were measured.

Serum corticosterone levels remained similar in both WT and tg mice across all diets, however local glucocorticoid actions, as measured by bone mRNA expression of 11β-HSD type 1, were elevated due to high-energy feeding in both WT (HFDhigh: ~2-fold, SFDhigh: ~3-fold) and tg mice (HFDhigh: ~2-fold, SFDhigh: ~3-fold). High-energy feeding, regardless of dietary fat content resulted in significantly increased fat mass in WT mice compared to WT chow-fed mice (SFDhigh:+88%, p<0.001, HFDhigh:+73%, p<0.005) and exhibited fasting hyperglycaemia and reduced insulin sensitivity. WT HFDhigh-fed mice also demonstrated pronounced glucose intolerance. Both high-energy diets induced significant tibial cortical volume loss to a similar extent (SFDhigh:-11%, p<0.005, HFDhigh:-14%, p<0.001). Surprisingly, tg mice that have abrogated osteoblast and osteocyte glucocorticoid signaling were protected from excessive fat accrual, insulin resistance, glucose intolerance and bone loss, despite consuming the same amount as their WT littermates on either high-energy diet.

Our data indicates that high-energy density rather than high dietary fat content is a major driver of metabolic dysfunction. Importantly, these effects appear to be mediated by glucocorticoid signaling in osteoblasts and osteocytes.

 

Nothing to Disclose: SK, HH, SJG, LT, MJS, HZ