Distinct functions of PPARγ isoforms in regulating adipocyte plasticity.

A better understanding of the mechanisms underlying obesity and its comorbidities is key to designing new therapies and treatments. PPARγ is a master regulator of adipocyte biology but the functions of its isoforms are poorly distinguished. Here we demonstrated that PPARγ1 is preferentially expressed in catabolic fat depots while PPARγ2 presents itself at a higher level in browning-resistant depots. PPARγ2, but not PPARγ1, responds to endogenous ligands to induce adipogenesis, and the isoforms regulate distinct sets of white and brown adipocyte genes. Moreover, PPARγ1 negatively correlates while PPARγ2 positively correlates with adiposity in human subcutaneous and visceral fat. These results together indicate that PPARγ1 and PPARγ2 have distinct functions in regulating adipocyte plasticity, and future research should take into account the binary roles of both isoforms in order to identify druggable gene targets and pathways relevant for treatment of metabolic disorders.

Genetic backgrounds determine brown remodeling of white fat in rodents.

OBJECTIVE: Genetic background largely contributes to the complexity of metabolic responses and dysfunctions. Induction of brown adipose features in white fat, known as brown remodeling, has been appreciated as a promising strategy to offset the positive energy balance in obesity and further to improve metabolism. Here we address the effects of genetic background on this process. METHODS: We investigated browning remodeling in a depot-specific manner by comparing the response of C57BL/6J, 129/Sv and FVB/NJ mouse strains to cold. RESULTS: Surprisingly, 129/Sv and FVB/NJ mice showed distinct brown remodeling features despite their similar resistance to metabolic disorders in comparison to the obesity-prone C57BL/6J mice. FVB/NJ mice demonstrated a preference of brown remodeling in inguinal subcutaneous white adipose tissue (iWAT), whereas 129/Sv mice displayed robust brown remodeling in visceral epididymal fat (eWAT). We further compared gene expression in different depots by RNA-sequencing and identified Hoxc10 as a novel "brake" of brown remodeling in iWAT. CONCLUSION: Rodent genetic background determines the brown remodeling of different white fat depots. This study provides new insights into the role of genetic variation in fat remodeling in susceptibility to metabolic diseases.