Over the course of eight years, Leibel's work ranged from studies of glycerol to the development of a radioisotopic technique for analysis of free fatty acid re-esterification in human adipose tissue to the metabolic characterization of obesity.

[10][11] After concluding that the tools of molecular genetics were key to moving his research forward and finding the obesity gene,[12] Leibel initiated a collaboration with Rockefeller University faculty member and molecular biologist Jeffrey Friedman in 1986, and began to assemble a team of researchers including Streamson C. Chua, Nathan Bahary, Don Siegel, Yiying Zhang, Ricardo Proenca and others.

Leibel obtained ongoing funding from the National Institutes of Health and other sources, allowing the team to develop and utilize new techniques in their research such as chromosome microdissection.

He was an Intern and Junior Resident in Pediatrics at Massachusetts General Hospital from 1967 to 1969, after which he served as a Major in the United States Army Medical Corps from 1969 to 1971.

His research is funded by the National Institutes of Health, the American Diabetes Association, the New York State Stem Cell Science Program, the Russell Berrie Foundation and the Leona M. and Harry B. Helmsley Charitable Trust, as well as Astra Zeneca.

Leibel's initial research was focused on adrenergic receptor-mediated effects on lipolysis, and on the control of fatty acid re-esterification in human adipose tissue.

[21][22] In addition to cloning the mouse mahoganoid mutation that modifies the obesity of Yellow mice, Leibel also developed a microassay system for quantifying the re-esterification pathway in human adipose tissue.

The laboratory has mapped, cloned and identified mutations in the obese and fatty genes in humans, rats, and mice and focuses on defining the physiological basis by which signaling networks regulate body size and composition.

The Leibel laboratory is also working to isolate additional human and rodent genes that influence body weight and the susceptibility to diabetes mellitus type 2 in the context of obesity.