A new study used several mouse mutants to study insulin receptor function specifically in the ventromedial nucleus of the hypothalamus (VMH), and found a role for VMH insulin signaling in promoting high-fat diet–induced obesity.

At the beginning of the twenty-first century, we are facing an unprecedented epidemic of impaired metabolic balance causing obesity, diabetes and associated disorders such as cardiovascular disease. Apart from the classical target organs of insulin signaling, such as liver, muscle or adipose tissue, there is growing evidence that the brain has an important role in maintaining energy, lipid and glucose homeostasis 1. Some of the key circuits responsible for nutrient sensing and the control of this metabolism are located in a specific brain area known as the ventromedial nucleus of the hypothalamus (VMH). This brain region was first described in 1903 by the father of modern neuroscience himself, Santiago Ramón y Cajal. With the help of advanced targeted mouse mutagenesis, Klöckener and colleagues set out 108 years later to functionally dissect key circuitry of this nucleus 2. In this issue of Nature Neuroscience, they report that insulin receptor signaling in VMH neuronal subpopulations expressing the reproductive function regulator steroidogenic factor 1 (SF-1) controls systemic metabolism and represents a key requirement for high-fat diet–induced obesity 2.