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Published on: May 28, 2021
Pleiotropic effects of cavin-1 deficiency on lipid metabolism
Shi-Ying Ding1, Mi-Jeong Lee, Ross Summer
1From the Departments of Biochemistry and.
Abstract:
Mice and humans lacking caveolae due to gene knock-out or inactivating mutations of cavin-1/PTRF have numerous pathologies including markedly aberrant fuel metabolism, lipodystrophy, and muscular dystrophy. We characterized the physiologic/metabolic profile of cavin-1 knock-out mice and determined that they were lean because of reduced white adipose depots. The knock-out mice were resistant to diet-induced obesity and had abnormal lipid metabolism in the major metabolic organs of white and brown fat and liver. Epididymal white fat cells from cavin-1-null mice were small and insensitive to insulin and β-adrenergic agonists resulting in reduced adipocyte lipid storage and impaired lipid tolerance. At the molecular level, the lipolytic defects in white fat were caused by impaired perilipin phosphorylation, and the reduced triglyceride accumulation was caused by decreased fatty acid uptake and incorporation as well as the virtual absence of insulin-stimulated glucose transport. The livers of cavin-1-null mice were mildly steatotic and did not accumulate more lipid after high-fat feeding. The brown adipose tissues of cavin-1-null mice exhibited decreased mitochondria protein expression, which was restored upon high fat feeding. Taken together, these data suggest that dysfunction in fat, muscle, and liver metabolism in cavin-1-null mice causes a pleiotropic phenotype, one apparently identical to that of humans lacking caveolae in all tissues.
Insights
Mice lacking caveolae due to cavin-1/PTRF gene defects exhibit metabolic dysfunction, including altered lipid metabolism and resistance to obesity. This highlights caveolae
Area of Science:
- Cell biology
- Metabolic diseases
- Molecular genetics
Background:
- Caveolae are specialized membrane microdomains involved in cellular signaling and transport.
- Defects in caveolae, caused by cavin-1/PTRF mutations, lead to various pathologies in mice and humans.
- Understanding the metabolic consequences of caveolae loss is crucial for disease insights.
Purpose of the Study:
- To comprehensively characterize the physiological and metabolic profile of cavin-1 knock-out mice.
- To elucidate the molecular mechanisms underlying metabolic abnormalities in these mice.
- To correlate the cavin-1 null phenotype with human conditions lacking caveolae.
Main Methods:
- Physiological and metabolic assessment of cavin-1 knock-out mice.
- Analysis of lipid metabolism in white adipose tissue, brown adipose tissue, and liver.
- Molecular analysis of adipocyte function, including insulin signaling and lipolysis.
- Evaluation of response to diet-induced obesity and high-fat feeding.
Main Results:
- Cavin-1 null mice were lean with reduced white adipose tissue depots and resistant to diet-induced obesity.
- Abnormal lipid metabolism was observed in white fat, brown fat, and liver.
- White adipocytes showed impaired insulin sensitivity, reduced lipid storage, and defective glucose transport.
- Molecular defects included impaired perilipin phosphorylation and reduced fatty acid uptake.
- Liver exhibited mild steatosis, and brown adipose tissue showed altered mitochondrial protein expression.
Conclusions:
- Cavin-1 deficiency leads to widespread metabolic dysfunction affecting fat, muscle, and liver.
- The observed phenotype in cavin-1 null mice mirrors human conditions characterized by a lack of caveolae.
- These findings underscore the critical role of caveolae and cavin-1 in maintaining metabolic homeostasis.
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