Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice

Aging usually involves the progressive development of certain illnesses, including diabetes and obesity. Due to incapacity to form new white adipocytes, adipose expansion in aged mice primarily depends on adipocyte hypertrophy, which induces metabolic dysfunction. On the other hand, brown adipose tissue burns fatty acids, preventing ectopic lipid accumulation and metabolic diseases. However, the capacity of brown/beige adipogenesis declines inevitably during the aging process. Previously, we reported that DNA demethylation in the Prdm16 promoter is required for beige adipogenesis. DNA methylation is mediated by ten-eleven family proteins (TET) using alpha-ketoglutarate (AKG) as a cofactor. Here, we demonstrated that the circulatory AKG concentration was reduced in middle-aged mice (10-month-old) compared with young mice (2-month-old). Through AKG administration replenishing the AKG pool, aged mice were associated with the lower body weight gain and fat mass, and improved glucose tolerance after challenged with high-fat diet (HFD). These metabolic changes are accompanied by increased expression of brown adipose genes and proteins in inguinal adipose tissue. Cold-induced brown/beige adipogenesis was impeded in HFD mice, whereas AKG rescued the impairment of beige adipocyte functionality in middle-aged mice. Besides, AKG administration up-regulated Prdm16 expression, which was correlated with an increase of DNA demethylation in the Prdm16 promoter. In summary, AKG supplementation promotes beige adipogenesis and alleviates HFD-induced obesity in middle-aged mice, which is associated with enhanced DNA demethylation of the Prdm16 gene

Retinoic acid induces white adipose tissue browning by increasing adipose vascularity and inducing beige adipogenesis of PDGFRα\u3csup\u3e+\u3c/sup\u3e adipose progenitors

© 2017 The Author(s). Formation of beige adipocytes within white adipose tissue enhances energy expenditure, which is a promising strategy to reduce obesity and prevent metabolic symptoms. Vitamin A and its bioactive metabolite, retinoic acid (RA), have regulatory roles in lipid metabolism. Here we report that RA induces white adipose tissue browning via activating vascular endothelial growth factor (VEGF) signaling. RA triggered angiogenesis and elicited de novo generation of platelet-derived growth factor receptor α positive (PDGFRα +) adipose precursor cells via VEGFA/VEGFR2 signaling. In addition, RA promoted beige/brown adipocyte formation from capillary networks in vitro. Using PDGFRα tracking mice, we found that the vascular system acted as an adipogenic repository by containing PDGFRα+ progenitors which differentiated into beige adipocytes under RA or VEGF164 treatments. Conditional knockout of VEGF receptors blocked RA-stimulated white adipose tissue browning. Moreover, the VEGFA and RA activated p38MAPK to enhance the binding of RA receptor to RA response elements of the Prdm16 promoter and upregulated Prdm16 transcription. In conclusion, RA induces white adipose tissue browning by increasing adipose vascularity and promoting beige adipogenesis of PDGFRα+ adipose progenitors