Attenuation of osteoblast and osteocyte glucocorticoid signalling protects from high-fat diet-induced obesity, insulin resistance and bone loss — ASN Events
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  3. Attenuation of osteoblast and osteocyte glucocorticoid signalling protects from high-fat diet-induced obesity, insulin resistance and bone loss

Attenuation of osteoblast and osteocyte glucocorticoid signalling protects from high-fat diet-induced obesity, insulin resistance and bone loss (#73)

Sarah Kim 1 , Holger Henneicke 1 2 , Sylvia J Gasparini 1 , Lee Thai 1 , Markus J Seibel 1 3 , Hong Zhou 1
  1. Bone Research Program, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia
  2. DFG-Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
  3. Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Concord, NSW, Australia

Overconsumption of energy-dense diets is a major public health challenge due its causal association with obesity, diabetes and poor skeletal health. Most animal studies examining diet-induced obesity and diabetes have focused solely on high-energy, high-fat diets. We therefore aimed to define whether the adverse health outcomes are due to the high-energy density or high-fat component of these diets. Since osteoblasts are involved in the regulation of overall energy balance, we also examined whether abrogating glucocorticoid signalling in osteoblasts protects mice from diet-induced metabolic and skeletal disturbances.

We utilised transgenic (tg) mice in which glucocorticoid signalling has been disrupted in osteoblasts/osteocytes via targeted overexpression of the glucocorticoid-inactivating enzyme, 11β-hydroxysteroid dehydrogenase type 2. Seven-week-old male tg mice and their wild-type (WT) littermates were fed ad libitum for 18-weeks one of the following diets: High-energy, standard-fat (fat=14% total-energy, 16.3kJ/g); high-energy, high-fat (fat=43% total-energy, 16.3kJ/g); standard-energy, high-fat (fat=43% total-energy, 13.8kJ/g) or standard-chow (fat=14% total-energy, 13.8kJ/g). At endpoint, body composition, glucose handling and bone mass were measured.

High-energy feeding, regardless of dietary fat content resulted in significantly increased fat mass in WT mice compared to WT chow-fed mice along with fasting hyperglycaemia and reduced insulin sensitivity. Both high-energy diets induced significant tibial trabecular and cortical volume loss to a similar extent. As expected, WT mice on the standard-energy, high-fat diet remained lean and insulin sensitive but displayed pronounced trabecular and cortical bone loss. Notably, tg mice were protected from high-energy diet-induced excessive fat accrual, insulin resistance, glucose intolerance and bone loss, despite consuming the same amount as their WT littermates on either high-energy diet and standard-energy, high-fat diet.

Conclusion: High-energy rather than high-fat content is a major driver of metabolic dysfunction, whereas high dietary fat results in bone loss. Importantly, these effects appear to be mediated by glucocorticoid signalling in osteoblasts and osteocytes.