Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Transient lipodystrophy protects against high-fat diet-induced bone volume loss in male mice (#65)

Emma J Buckels 1 2 , Randall F D'Souza 2 3 , Troy L Merry 2 3 , Brya G Matthews 1 2
  1. Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand
  2. Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
  3. Department of Nutrition, University of Auckland, Auckland, New Zealand

Adipose tissue is a key regulator of glucose homeostasis and interacts with the skeleton locally and systemically. Recent severe murine lipodystrophy models, where white and brown adipose tissue (WAT and BAT) are eliminated, demonstrated massive increases in trabecular and cortical bone when mice were fed a chow diet, despite marked metabolic dysfunction. A high-fat diet (HFD) has repeatedly been shown to have adverse effects on bone in rodents. Our study aimed to determine whether an HFD would affect trabecular or cortical bone microarchitecture in a model of inducible transient lipodystrophy.

 

Male Adiponectin-CreER/IRflox/flox (Adipo-IR-KO) mice were treated with tamoxifen at 8-weeks of age. Adiponectin-CreER primarily targets mature adipocytes. Signalling through the insulin receptor (IR) is critical for adipocyte survival in WAT and BAT. Therefore, tamoxifen-induced deletion of IR in adiponectin-expressing cells leads to marked but transient depletion of adipose depots that are gradually replenished by IR+ progenitors.

 

Following a 12-week recovery period, Adipo-IR-KO or wild-type (WT) control mice were switched to an HFD (60% kcal from fat). Tissues were collected from a subset of animals prior to HFD-feeding or after 20-weeks of HFD. Metabolic phenotypes were evaluated throughout the study, and bone phenotypes were evaluated by microCT.

 

Adipo-IR-KO mice experienced marked hyperglycemia in the days following adipocyte-specific IR knockout (Figure 1). WT and Adipo-IR-KO had similar blood glucose concentrations and trabecular bone volume by 4-weeks post IR depletion. After 20-weeks of HFD, trabecular bone volume was 25% higher (p=0.03), and trabecular number was increased 18% (p=0.04) in Adipo-IR-KO vs. WT mice. Cortical bone was similar between groups.

 

This study demonstrated that transient lipodystrophy 12-weeks before the induction of HFD prevented HFD-induced bone loss in male mice. Following this novel finding, work is underway to understand the crosstalk between adipose tissue and the skeleton.

 

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