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 postprandial state. However, this build-up of triglyceriderich 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.

Extensive vascularization of developing mouse ovaries revealed by caveolin‐1 expression

“…The function of caveolae remains controversial, but they are implicated in lipid regulation (Razani et al, 2002), endocytosis/transcytosis, and signal transduction (Okamoto et al, 1998;Drab et al, 2001;Matveev et al, 2001;Schlegel and Lisanti, 2001). Caveolae are particularly abundant in adipocytes and endothelial cells (Scherer et al, 1995).…”

Caveolin proteins and estrogen signaling in the brain

“…Disruption of CAV2 expression does not affect caveolae formation in vivo [33], inasmuch it is hypothesized that CAV2 only forms caveolae as hetero-oligomers with CAV1, and not in isolation [34]. In comparison, knockout of either CAV1 or CAV3 results in a loss of caveolae formations in the specific cell type for which they are expressed [35,36]. Notably, it was originally believed that expression of CAV3 was restricted to skeletal and smooth muscle cells [26,[37][38][39].…”

Impaired contractility and detrusor hypertrophy in cavin-1-deficient mice

“…The functional roles of caveolae are diverse and tissue-specific and include cellular processes such as lipid and glucose homeostasis and endocytosis (Capozza et al, 2005;Razani et al, 2002). Caveolae are moreover considered to play an important but complex role in cellular signalling through their ability to sequester signalling molecules (Bastiani and Parton, 2010).…”