Cold Induced Depot-Specific Browning in Ferret Aortic Perivascular Adipose Tissue.

Bàrbara Reynés,Jaap Keijer,Enzo Ceresi,Andreu Palou,Paula Oliver,Evert M Van Schothorst

doi:10.3389/fphys.2019.01171

Abstract

Brown adipose tissue is responsible for facultative thermogenesis to produce heat and increase energy expenditure in response to proper stimuli, e.g., cold. Acquisition of brown-like features (browning) in perivascular white adipose tissue (PVAT) may protect against obesity/cardiovascular disease. Most browning studies are performed in rodents, but translation to humans would benefit from a closer animal model. Therefore, we studied the browning response of ferret thoracic aortic PVAT (tPVAT) to cold. We performed global transcriptome analysis of tPVAT of 3-month-old ferrets acclimatized 1 week to 22 or 4°C, and compared the results with those of inguinal subcutaneous adipose tissue. Immunohistochemistry was used to visualize browning. Transcriptome data revealed a stronger cold exposure response of tPVAT, including increased expression of key brown/brite markers, compared to subcutaneous fat. This translated into a clear white-to-brown remodeling of tPVAT, with the appearance of multilocular highly UCP1-stained adipocytes. The pathway most affected by cold exposure in tPVAT was immune response, characterized by down-regulation of immune-related genes, with cardio protective implications. On the other hand, subcutaneous fat responded to cold by increasing energy metabolism based on increased expression of fatty acid oxidation and tricarboxylic acid cycle genes, concordant with lower inguinal adipose tissue weight in cold-exposed animals. Thus, ferret tPVAT responds to cold acclimation with a strong induction of browning and immunosuppression compared to subcutaneous fat. Our results present ferrets as an accessible translational animal model displaying functional responses relevant for obesity and cardiovascular disease prevention.

Highlights

Adipose tissue has different biological functions, including adaptation to low ambient temperatures (Cinti, 2005)
Ferret as a Model for Adipose Browning Research is mediated by the uncoupling protein 1 (UCP1) (Cannon and Nedergaard, 2004) present in the inner mitochondrial membrane of brown adipocytes, which acts as a proton conductor, dissipating the proton gradient generated by the respiratory chain as heat (Palou et al, 1998)
These animals present dispersed multilocular adipocytes with modest levels of UCP1 in different adipose tissue depots, which increase by cold exposure and dietary stimuli, mainly in the retroperitoneal depot (Fuster et al, 2009; Sánchez et al, 2009). These data point to ferrets as an interesting alternative model to rodents to be used in studies of thermogenesis, as we have reported in a revision on white adipose tissue browning (Bonet et al, 2013)

Summary

Introduction

Adipose tissue has different biological functions, including adaptation to low ambient temperatures (Cinti, 2005). Cold exposure activates brown adipose tissue (BAT), which uses circulating free fatty acids produced by catabolic lipid metabolism of WAT to produce heat representing nonshivering or facultative thermogenesis (Cannon and Nedergaard, 2004; Cinti, 2005) It is well known that cold exposure activates BAT and results in a remarkable induction of UCP1-positive brown fat-like adipocytes in WAT, the so-called beige or brite cells (Ishibashi and Seale, 2010; Petrovic et al, 2010) This process, known as browning is widely characterized in rodents (Cousin et al, 1992; García-Ruiz et al, 2015) and could contribute to energy dissipation as heat. It has been proposed that, in humans, brown adipocytes could be, beige adipocytes, arising as result of WAT browning in response to proper stimuli (Wu et al, 2012)

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