title: Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities.
abstract: Caveolae organelles and caveolin-1 protein expression are most abundant in adipocytes and endothelial cells. Our initial report on mice lacking caveolin-1 (Cav-1) demonstrated a loss of caveolae and perturbations in endothelial cell function. More recently, however, observation of the Cav-1-deficient cohorts into old age revealed significantly lower body weights, as compared with wild-type controls. These results suggest that Cav-1 null mice may have problems with lipid metabolism and/or adipocyte functioning. To test this hypothesis directly, we placed a cohort of wild-type and Cav-1 null mice on a high fat diet. Interestingly, despite being hyperphagic, Cav-1 null mice show overt resistance to diet-induced obesity. As predicted, adipocytes from Cav-1 null null mice lack caveolae membranes. Early on, a lack of caveolin-1 selectively affects only the female mammary gland fat pad and results in a near complete ablation of the hypo-dermal fat layer. There are also indications of generalized adipose tissue pathology. With increasing age, a systemic decompensation in lipid accumulation occurs resulting in dramatically smaller fat pads, histologically reduced adipocyte cell diameter, and a poorly differentiated/hypercellular white adipose parenchyma. To gain mechanistic insights into this phenotype, we show that, although serum insulin, glucose, and cholesterol levels are entirely normal, Cav-1 null mice have severely elevated triglyceride and free fatty acid levels, especially in the post-prandial state. However, this build-up of triglyceride-rich chylomicrons/very low density lipoproteins is not due to perturbed lipoprotein lipase activity, a major culprit of isolated hypertriglyceridemia. The lean body phenotype and metabolic defects observed in Cav-1 null mice are consistent with the previously proposed functions of caveolin-1 and caveolae in adipocytes. Our results show for the first time a clear role for caveolins in systemic lipid homeostasis in vivo and place caveolin-1/caveolae as major factors in hyperlipidemias and obesity.
authors.affiliation: Department of Molecular Pharmacology, The Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
authors.forename: Terry P
authors.initials: TP
authors.lastname: Combs
authors.forename: Xiao Bo
authors.initials: XB
authors.lastname: Wang
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Robert G
authors.initials: RG
authors.lastname: Russell
authors.forename: Maomi
authors.initials: M
authors.lastname: Li
authors.forename: Baiyu
authors.initials: B
authors.lastname: Tang
authors.forename: Linda A
authors.initials: LA
authors.lastname: Jelicks
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D004032:Diet; D004591:Electrophoresis, Polyacrylamide Gel; D005247:Feeding Behavior; D005260:Female; D006706:Homeostasis; D015228:Hypertriglyceridemia / Q000235:genetics*; D015151:Immunoblotting; D007700:Kinetics; D008049:Lipase / Q000097:blood; D050356:Lipid Metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012737:Sex Factors; D013997:Time Factors
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D008049:Lipase