Investigating the impact of subcutaneous and visceral adiposity on metabolism using an adipose tissue transplantation model

Abstract

Intra-abdominal (AB) obesity is associated with a higher risk of diabetes than subcutaneous (SC) obesity. To determine whether this is due to differences in anatomical location or intrinsic differences in fat depots, the metabolic effects of transplantation of SC or AB fat into the SC or AB space of recipient mice were determined.

Donor inguinal (SC) and epididymal (AB) fat was transplanted into the SC (SC-SC and AB-SC) or AB (SC-AB and AB-AB) space in high fat-fed (45% calories from fat) male C57BL6/J mice. Sham-operated mice underwent surgery without fat transplantation (SHAM). 11-13 weeks after transplantation metabolic studies were performed and adipose tissue harvested for analysis including microarray.

Mice receiving SC-AB grafts displayed significantly reduced fat mass, in both transplanted and endogenous fat depots, and improved glucose tolerance compared with SHAM. These metabolic effects were not observed in mice receiving SC-SC, AB-SC or AB-AB grafts. Microarray analysis of transplanted and endogenous fat depots revealed increased expression of genes controlled by the transcription factor myocyte enhancer factor 2 (MEF2-genes) in SC-AB grafts and the endogenous inguinal adipose tissue (ENDOG-SC) from mice receiving a SC-AB graft. Increased uncoupling protein-1 (UCP-1) gene expression was observed uniquely in ENDOG-SC fat.

At 13 weeks post-transplantation SC-AB grafts had decreased in mass. Failure of SC grafts to expand in the AB compartment suggests that cross-talk between adipocyte and non-adipocyte components of adipose tissue is depot-specific. Lectin affinity chromatography combined with partial metabolic labelling and mass spectrometry determined quantitative differences in the secretomes of SC and AB whole adipose tissue, preadipocytes and microvascular endothelial cells, suggesting intrinsic depot-specific differences are present in all cell types within adipose tissue.

These findings suggest a unique beneficial metabolic effect of SC-AB transplantation that is mediated by a secreted factor acting uniquely on SC fat to increase expression of MEF2-genes and UCP-1. As chronic B3-adrenergic stimulation of white adipose tissue increases UCP-1 and MEF2 expression is increased by adrenergic stimulation in non-adipose adult tissues, increased adrenergic-stimulation of subcutaneous fat is a putative mechanism. The identity of the secreted factor is important as it may provide a novel treatment for obesity-induced metabolic disease.