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Friedman studies the molecular mechanisms that regulate food intake and body weight. Genetic studies in mice led him to identify leptin, a hormone made by fat tissue that plays a key role in controlling appetite and weight. His current work explores the mechanisms by which leptin mediates these functions, and seeks to identify other key regulators of body weight.

Leptin maintains body weight within a relatively narrow range. Increased fat mass increases leptin levels, which in turn reduces body weight; decreased fat mass decreases leptin levels and increases body weight. Defects in the leptin gene are associated with severe obesity, and leptin treatment normalizes weight in these patients. Leptin also improves the severe diabetes and abnormal lipids in patients with lipodystrophy, and is now an FDA-approved treatment for this condition.

Neural Circuits Regulating Food Intake

Leptin acts on discrete sets of neurons to regulate appetite, and has powerful effects on reproduction, immune function, other endocrine systems, and the function of many hormones. Friedman and his colleagues are delineating the precise neuronal effects of leptin and the mechanisms by which it alters behavior. The lab has found that leptin reduces food intake by decreasing the pleasure associated with food, and that it modulates the activity of neurons in the hypothalamus that express a peptide called MCH, which plays a key role in sensing the reward value of food. The lab has also identified neurons that regulate appetite; modulating these neurons’ activity can alter body weight, thus providing a potential new approach for treating obesity. Still other experiments have delineated neural circuits that link learned cues to increased food intake, and the mechanisms that decrease food intake after stress.

Regulation of Leptin Gene Expression

The Friedman lab has identified DNA regulatory sequences and a fat-specific long non-coding RNA that control leptin gene expression. They found that mice with a mutation in this RNA, called LncOb, show increased fat mass with reduced leptin levels. Mice that lack LncOb have lower leptin levels than controls do and become more obese on a high fat diet, but show significant weight loss after leptin treatment. These studies suggest that people with obesity and low leptin levels might respond similarly.

Regulation of Fat Innervation

Leptin interacts with the sympathetic nervous system, which plays an important role in regulating how much energy fat cells store or burn. Recent studies have shown that fat in leptin-deficient animals almost completely lacks sympathetic nerves, and that leptin treatment restores these nerves within 7 to 10 days. Friedman’s lab has delineated the entire neural circuit responsible for these leptin-induced changes. It involves leptin-mediated activation of neurons in the hypothalamus that express a protein called BDNF. Blocking BDNF signaling from the hypothalamus to the spinal cord blunts leptin’s ability to induce nerve growth in fat. Current studies seek to understand how BDNF induces adipose tissue nerve growth.

Genetic Studies of Metabolic Disease in Humans

The Friedman lab is conducting genetic studies of consanguineous families with severe obesity or a hormonal condition called polycystic ovary syndrome (PCOS), in collaboration with Tayfun Özçelik at Bilkent University in Ankara, Turkey. The team is analyzing the DNA sequences from these populations, in collaboration with the Lifton laboratory, to identify DNA mutations that contribute to differences in weight or that lead to PCOS.