Abstract
Caveolin-1 (CAV1) is an important regulator of adipose tissue homeostasis. In the present study we examined the impact of CAV1 deficiency on the properties of mouse adipose tissue both in vivo and in explant cultures during conditions of metabolic stress. In CAV1−/− mice fasting caused loss of adipose tissue mass despite a lack of hormone-sensitive lipase (HSL) phosphorylation. In addition, fasting resulted in increased macrophage infiltration, enhanced deposition of collagen, and a reduction in the level of the lipid droplet protein perilipin A (PLIN1a). Explant cultures of CAV1−/− adipose tissue also showed a loss of PLIN1a during culture, enhanced secretion of IL-6, increased release of lactate dehydrogenase, and demonstrated increased susceptibility to cell death upon collagenase treatment. Attenuated PKA-mediated signaling to HSL, loss of PLIN1a and increased secretion of IL-6 were also observed in adipose tissue explants of CAV1+/+ mice with diet-induced obesity. Together these results suggest that while alterations in adipocyte lipid droplet biology support adipose tissue metabolism in the absence of PKA-mediated pro-lipolytic signaling in CAV1−/− mice, the tissue is intrinsically unstable resulting in increased susceptibility to cell death, which we suggest underlies the development of fibrosis and inflammation during periods of metabolic stress.
Highlights
Dysregulation of systemic lipid levels plays an important role in the development of numerous metabolic disorders including obesity and lipodystrophy [1,2,3]
These data suggest that hydrolysis of stored triglycerides during fasting in wild type mice is catalysed by lipid droplet-associated, phosphorylated hormone-sensitive lipase (HSL), whereas the hydrolysis of triglycerides in CAV12/2 mice occurs through a distinct mechanism that does not require HSL phosphorylation by protein kinase A (PKA)
As phosphorylation of HSL is required for its translocation to the lipid droplet surface [27], these data indicate a general defect in PKA-mediated pro-lipolytic mechanisms in CAV12/2 mice in response to both fasting and to acute adrenergic stimulation
Summary
Dysregulation of systemic lipid levels plays an important role in the development of numerous metabolic disorders including obesity and lipodystrophy [1,2,3]. Adipose tissue is central to lipid regulation, facilitating both the storage of fatty acids as neutral lipids within the lipid droplets (LDs) of adipocytes, and regulating the release of fatty acids in response to both acute and chronic stimuli. In metabolic disorders these essential functions of adipose tissue are compromised. During fasting the mobilization of fatty acids can be chronically activated through a combination of increased adrenaline and glucagon and reduced levels of insulin [10] In addition cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) have been shown to promote lipolysis both in vitro and in vivo [11]
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