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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #113615
Title: ABSENCE OF PERILIPIN PRODUCES GENETIC LEANNESS AND REVERSES OBESITY IN DB/DB MICE

Author
item MARTINEZ-BOTAS, JAVIER - BAYLOR COLLEGE OF MED
item ANDERSON, JOHN - BAYLOR COLLEGE OF MED
item TESSIER, DARIN - BAYLOR COLLEGE OF MED
item LAPILLONNE, ALEXANDRE - USDA CHILD NUTR RES CNTR
item CHANG, BENNY - BAYLOR COLLEGE OF MED
item QUAST, MICHAEL - MARINE BIOMED INSTITUTE
item BORENSTEIN, DAVID - SEALY CNTR UT MED BRANCH
item CHEN, KUANG-HUA - BAYLOR COLLEGE OF MED
item CHAN, LAWRENCE - BAYLOR COLLEGE OF MED

Submitted to: Nature Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/14/2000
Publication Date: N/A
Citation: N/A

Interpretive Summary: Perilipin is a protein that forms a coating around the fat droplets in fat cells. It acts as a barrier to an enzyme called HSL (hormone-stimulated lipase), which hydrolyzes lipid droplets and releases triglyceride. We generated a knockout mouse by inserting a disruption in the gene responsible for the synthesis of perilipin so that it is effectively absent in this mouse. Compared to a control mouse, the knockout mouse was leaner, more muscular, had a much lower level of total lipids, and higher energy expenditure. It was also cold-sensitive except when eating because it had less fat under the skin. In addition, the lipid droplets in this mouse's fat cells were much smaller, and the HSL activity was much higher without the perilipin around the droplets. We then crossed the knockout mouse with a db/db mouse, which is a model for obesity. We found that the lack of perilipin in the knockout parent apparently reversed the obesity so that it was not present in the offspring. Perilipin obviously is an important protein to target in future studies to reduce obesity. Based on our findings, we believe that agents which inactivate perilipin may be useful as anti-obesity drugs. Since obesity is increasing in the United States at epidemic proportions among both young and old, this achievement is a real breakthrough in an area of major health concern.

Technical Abstract: Obesity is a disorder of energy balance. Hormone-sensitive lipase (HSL) mediates the hydrolysis of triacylglycerol, the major form of stored energy in the body. Perilipin (plin), an adipocyte protein, has been postulated to modulate HSL activity. We show that targeted disruption of perilipin results in healthy mice which exhibit constitutively activated fat-cell HSL. Compared to controls, plin -/- mice consume more food but have normal body weight, are much leaner and more muscular, have 62% smaller white adipocytes, exhibit elevated basal lipolysis that is resistant to beta- adrenergic agonist stimulation, and are cold-sensitive except when fed. They are also resistant to diet-induced obesity. Breeding the plin -/- alleles into db/db mice reverses the obesity by significantly increasing the metabolic rate of the latter. These results demonstrate a role for perilipin in reining in basal HSL activity and regulating lipolysis and energy balance; thus, agents that inactivate perilipin may prove useful as anti-obesity medications.