Work led by Prof Sadaf Farooqi’s team, in collaboration with Yong Xu’s lab (Baylor College of Medicine, Houston), published today in Nature Communications describes the role of Steroid Receptor Coactivator (SRC)-1 in modulating leptin signalling in hypothalamic Pomc neurons. The team showed that conditional knock-out of SRC-1 in Pomc neurons leads to increased food intake and weight gain.
They found fifteen rare heterozygous variants in SRC-1 in people with severe obesity which impaired leptin-mediated Pomc reporter activity in cells. To directly test whether these variants could contribute to the regulation of energy homeostasis, a knock-in mouse model of one of the human variants was generated – this mouse exhibited reduced Pomc expression, increased food intake and weight gain. This work makes the case that SRC-1 is an important regulator of body weight in mice and humans.