Abstract

The ROR α‐deficient staggerer (sg/sg) mouse is lean and resistant to diet‐induced obesity. Its thermogenic activity was shown to be increased not only in brown adipose tissue (BAT), but also in subcutaneous white adipose tissue (WAT) where UCP1 content was enhanced, however, without Prdm16 coexpression. Our observation of partial multilocular lipid morphology of WAT in sg/sg mice both in the inguinal and perigonadal sites led us to focus on the phenotype of both fat depots. Because ROR α is a nuclear factor acting in the clock machinery, we looked at the circadian expression profile of genes involved in thermogenesis and browning in WAT and BAT depots of sg/sg and WT mice, through real‐time quantitative PCR and western blotting. This 24‐h period approach revealed both a rhythmic expression of thermogenic genes in WAT and an increased browning of all the WAT depots tested in sg/sg mice that indeed involved the canonical browning process (through induction of Pgc‐1α and Prdm16). This was associated with an enhanced isoproterenol‐induced oxygen consumption rate of WAT explants from sg/sg mice, which was reproducible in WT explants by treatment with a ROR α inverse agonist SR 3335, that induced a parallel increase in the UCP1 protein. Inhibitors of browning differentiation, such as TLE3 and RIP140, could be new targets of ROR α that would be rather implicated in the whitening of adipocytes. Our study showed the pivotal role of ROR α as an inhibitor of the thermogenic program in WAT, the role that could be counteracted in vivo with the ROR α antagonists currently in development.

Highlights

  • Brown adipocytes are thermogenic cells predominantly found in brown adipose tissue (BAT)

  • Browning of white adipose tissue (WAT) was functionally assessed by the observation of an increased oxygen consumption rate (OCR) in response to isoproterenol

  • While this browning was higher in inguinal subcutaneous adipose tissue (IAT) than in epididymal adipose tissue (EAT) in male, we discovered a substantial uncoupling protein 1 (UCP1) enrichment in perigonadal WAT of female sg/sg mice

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Summary

Introduction

Brown adipocytes are thermogenic cells predominantly found in brown adipose tissue (BAT). The induction of the thermogenic program of WAT, a process named browning (resulting in beige WAT), is thought to be a potential way for treatment of obesity and its related metabolic disturbances (Dulloo 2011). The discovery of new molecular mechanisms of browning is fundamental in order to understand this process that favors the elimination of fatty acids rather than their excessive storage, storage which in turn leads to adipocyte hypertrophy and subsequent tissue dysfunctions observed in obese states. Vitamins, and dietary lipids, NRs coordinate molecular genetic programs that regulate lipid and carbohydrate metabolism (Chawla et al 2001). The orphan nuclear factor retinoid-related orphan receptor a (RORa), for example, is involved in several processes that are deregulated in pathologically expanding adipose tissue such as inflammation,

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