Hedgehog signaling via Gli2 prevents obesity induced by high fat diet in adult mice

Obesity poses a significant risk of developing type II diabetes and other diseases. Hedgehog (Hh) signaling has been shown to inhibit adipose tissue development, but its effect on diet-induced obesity during postnatal life is not known. Here by genetically activating Hh signaling in the adipocyte lineage of postnatal mice following doxycycline (Dox) withdrawal, we show that the mice are resistant to high-fat-diet-induced obesity and exhibit superior glucose tolerance and insulin sensitivity. Consistent with the reduced hypertrophy of adipocytes in the mutant mice, Hh suppresses the conversion of glucose to lipid in adipocytes. Moreover, Hh signaling inhibits adipocyte differentiation from the mesenchymal progenitors mainly through Gli2 that induces the transcription of multiple Wnt genes. Pharmacological inhibition of Porcupine, an acyltransferase essential for Wnt secretion, alleviates the suppression of adipocyte differentiation by Hh. Thus, targeted activation of the Hh pathway may be an effective approach to combat diet-induced obesity and the associated metabolic diseases.