p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Abstract

Scope The tumor suppressor p107, a pocket protein member of the retinoblastoma susceptibility protein family, plays an important role in the cell cycle and cellular adipocyte differentiation. Nonetheless, the mechanism by which it influences whole body Energy homeostasis is unknown. Methods and Results The phenotype of p107 knockout (KO) mixed‐background C57BL6/129 mice phenotype is studied by focusing on the involvement of white and brown adipose tissue (WAT and BAT) in energy metabolism. It is shown that p107 KO mice are leaner and have high‐fat diet resistence. This phenomenon is explained by an increase of energy expenditure. The higher energy expenditure is caused by the activation of thermogenesis and may be mediated by both BAT and the browning of WAT. Consequently, it leads to the resistance of p107 KO mice to high‐fat diet effects, prevention of liver steatosis, and improvement of the lipid profile and glucose homeostasis. Conclusion These data allowed the unmasking of a mechanism by which a KO of p107 prevents diet‐induced obesity by increasing energy expenditure via increased thermogenesis in BAT and browning of WAT, indicating the relevance of p107 as a modulator of metabolic activity of both brown and white adipocytes. Therefore, it can be targeted for the development of new therapies to ameliorate the metabolic syndrome.

Cissus Quadrangularis enhances UCP1 mRNA, indicative of white adipocyte browning and decreases central obesity in humans in a randomized trial

“…Although many studies in mice revealed that browning of adipose tissue was associated with increased thermogenesis and energy expenditure leading to weight loss [37][38][39] , the browning effect of adipose tissue associated with increased energy expenditure and weight loss in humans is still under debate. After mild cold exposure, human subjects with high brown adipose tissue mass increased daily energy expenditure by 14.7% while subjects with low brown adipose tissue mass slightly increased their energy expenditure by 0.4% 40 .…”

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

“…Several TFs and activating cofactors are shown to have negative effects on beige/brown fat formation and function including Hes1 [ 122 ], Irx3 [ 123 ], Irx5 [ 123 ], Rip140 [ 124 , 125 , 126 ], Tle3 [ 127 ], Zfp423 [ 128 , 129 ], Hoxc8 [ 130 ], Hoxc10 [ 131 ], Twist1 [ 132 ], Foxa3 [ 133 , 134 ], Foxo1 [ 135 , 136 ], Foxp1 [ 137 ], Rb [ 138 ], Src2 (Tif2), Smad3 [ 139 ], Usf1 [ 140 ], Mrtfa [ 141 ], Lxr [ 142 ], and P107 [ 143 , 144 , 145 ]. Transcriptional repressors such as Ctbp1 and Ctbp2 [ 90 , 146 ] suppress the WAT gene expression and promote the browning of WAT.…”

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

“…Several TFs and activating cofactors are shown to have negative effects on beige/brown fat formation and function including Hes1 [122], Irx3 [123], Irx5 [123], Rip140 [124][125][126], Tle3 [127], Zfp423 [128,129], Hoxc8 [130], Hoxc10 [131], Twist1 [132], Foxa3 [133,134], Foxo1 [135,136], Foxp1 [137], Rb [138], Src2 (Tif2), Smad3 [139], Usf1 [140], Mrtfa [141], Lxr [142], and P107 [143][144][145]. Transcriptional repressors such as Ctbp1 and Ctbp2 [90,146] suppress the WAT gene expression and promote the browning of WAT.…”