Thermogenic crosstalk occurs between adipocytes from different species

Chen Gilor,Kathleen Ham,Aejin Lee,Paolo Fadda,No-Joon Song,Christopher A Adin,Ouliana Ziouzenkova,Kefeng Yang,James Lee,Claire Herbert,Ryan Jennings

doi:10.1038/s41598-019-50628-9

Abstract

Visceral obesity increases risks for all-cause mortality worldwide. A small population of thermogenic adipocytes expressing uncoupling protein-1 (Ucp1) regulates energy dissipation in white adipose tissue (WAT) depots. Thermogenic adipocytes subsets decrease obesity in mice, but their efficacy has not been tested in obese large animals. Here we enclosed murine subcutaneous adipocytes with and without engineered thermogenic response in biocompatible microcapsules and implanted them into the left and right side of the visceral falciform depot in six obese dogs. After 28 days of treatment, dogs have markedly reduced waist circumference, body weight, and fat mass. Ucp1 expression in canine WAT was increased at sites implanted with thermogenic vs. wild type murine adipocytes. This site-specific thermogenic remodeling of canine tissue by thermogenic murine adipocytes suggests evolutionary conserved paracrine regulation of energy dissipation across species. These findings have translational potential aimed to reduce deleterious WAT depots in humans and pets.

Highlights

In mice, the deleterious properties of visceral white adipose tissue (WAT) could be improved after transplantation of subcutaneous adipocytes into visceral WAT12
We compare two types of murine subcutaneous adipocytes (1) Wild type (WT) adipocytes and (2) A1KO adipocytes with thermogenic phenotype that was previously characterized extensively in vitro and in vivo[15,23]
We demonstrate that implantation of a small subset of encapsulated A1KO adipocytes into the visceral fat of obese dogs induced local thermogenic remodeling of visceral fat

Summary

Introduction

The deleterious properties of visceral WAT could be improved after transplantation of subcutaneous adipocytes into visceral WAT12. Many genes can affect the thermogenic potential of adipocytes[18], the silencing of aldehyde dehydrogenase a1 (Aldh1a1, alias Raldh1) has a unique mechanism of action via production of neuroendocrine factors that mediate global thermogenic remodeling of WAT17 This enzyme metabolizes retinaldehydes produced in the vitamin A pathway[19] with reduced specificity towards other aldehydes[20] that changes intracellular[15] and paracrine[21] thermogenic responses in adipocytes. To assess the translational potential of subsets of thermogenic adipocytes, it is critical to evaluate their survival, function, biocompatibility, and efficacy in the regulation of energy homeostasis in large animals with a mixed genetic background In this proof-of-concept study we demonstrate that a small population of thermogenic and subcutaneous murine adipocytes can reduce weight and waist circumference in obese dogs

Methods

Results

Conclusion