Caveolin Is an Activator of Insulin Receptor Signaling

Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin‐3 (CAV3). We further test whether haploinsufficiency for CAV3 increases the susceptibility to high‐fat‐induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of the IR. We show that haploinsufficiency for CAV3 increases susceptibility to palmitate‐induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show that CAV3 and IR directly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin‐stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin‐stimulated glucose uptake in HL‐1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin‐independent serine phosphorylation of IRS‐1 by 35%. In addition, we found lipid induced downregulation of CD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss of CAV3 interferes with downstream insulin signaling and lipid uptake, implicating CAV3 as a regulator of the IR and regulator of lipid uptake in the heart.

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“…1998; Yamamoto et al. 1998). Our co‐IP and FRET data in HL‐1 cardiomyocytes provide further support that the IR and CAV3 are in close proximity.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance

et al. 2016

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“…SCP-2) cholesterol binding proteins preferentially donate or extract cholesterol from cholesterol-rich, but not cholesterol-poor, microdomains (26,27,136,137,172). The microdomain/lipid raft concept, despite controversy in details, provides a framework for biologists studying localization and function of membrane protein receptors, transporters, and downstream signaling molecules that regulate uptake of cholesterol (86,87,, fatty acids (240)(241)(242), glucose (243)(244)(245)(246)(247)(248)(249)(250)(251)(252)(253)(254), and other activities (216,(255)(256)(257)(258)(259)(260). Cholesterol-poor microdomain preferring cholesterol analogs: BODIPY-coprostanol analog 3; BODIPY-cholesterol analog LZ110a; 22-NBD-cholesterol.…”

Section: Summary and Discussionmentioning

confidence: 99%

Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

McIntosh

Atshaves

Huang

et al. 2008

Lipids

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Cholesterol itself has very few structural/chemical features suitable for real-time imaging in living cells. Thus, the advent of dehydroergosterol [ergosta-5,7,9(11),22-tetraen-3β-ol, DHE] the fluorescent sterol most structurally and functionally similar to cholesterol to date, has proven to be a major asset for real-time probing/elucidating the sterol environment and intracellular sterol trafficking in living organisms. DHE is a naturally-occurring, fluorescent sterol analog that faithfully mimics many of the properties of cholesterol. Because these properties are very sensitive to sterol structure and degradation, such studies require the use of extremely pure (>98%) quantities of fluorescent sterol. DHE is readily bound by cholesterol-binding proteins, is incorporated into lipoproteins (from the diet of animals or by exchange in vitro), and for real-time imaging studies is easily incorporated into cultured cells where it co-distributes with endogenous sterol. Incorporation from an ethanolic stock solution to cell culture media is effective, but this process forms an aqueous dispersion of dehydroergosterol crystals which can result in endocytic cellular uptake and distribution into lysosomes which is problematic in imaging DHE at the plasma membrane of living cells. In contrast, monomeric DHE can be incorporated from unilamellar vesicles by exchange/fusion with the plasma membrane or from DHE-methyl-β-cyclodextrin (DHE-MβCD) complexes by exchange with the plasma membrane. Both of the latter techniques can deliver large quantities of monomeric dehydroergosterol with significant distribution into the plasma membrane. The properties and behavior of DHE in protein-binding, lipoproteins, model membranes, biological membranes, lipid rafts/caveolae, and real-time imaging in living cells indicate that this naturally-occurring fluorescent sterol is a useful mimic for probing the properties of cholesterol in these systems. Keywordsdehydroergosterol; cholesterol; ergosterol; fluorescent sterols; microscopy Historical PerspectiveIn order to resolve the dynamics and factors governing cholesterol trafficking within cells, it is important to recognize that the cholesterol molecule has very few polar constituents (Fig. 1A). Consequently, cholesterol is poorly soluble in aqueous environments such as cytosol as evidenced by critical micellar concentrations of cholesterol and other sterols being very low, *To whom correspondence should be addressed: Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 862-1433, FAX: (979) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript near 20-30 nM (1-5). The physiological impact of cholesterol's low aqueous solubility is that spontaneous cholesterol desorption from the cytofacial leaflet of the plasma membrane or lysosomal membrane into the cytosol for transfer to intracellular sites for esterification, oxidation, or secretion is extremely slow (t 1/2 3 hours-days) (6-9). Therefore, it is important to resolve factors...

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“…Cav-1 expression pattern is similar to that observed in adipose tissue in previous studies, while Cav-2 behaves in the opposite way [26,27], suggesting that they are inversely regulated. In adipocytes Cav-1 co-localizes with IR and positively regulates the activation of IR upon insulin stimulation [28], but the role of Cav-1 in muscle insulin signalling has received little attention, probably because Cav-3 is the musclespecific isoform. Our results suggest that insulin signalling could be downregulated due to a decrease in Cav-1 and IR phosphorylation, in accordance to other authors that have reported reduced muscle insulin-stimulated glucose uptake after siRNA downregulation of Cav-1 [5].…”

Section: Discussionmentioning

confidence: 99%

Time‐dependent regulation of muscle caveolin activation and insulin signalling in response to high‐fat diet

et al. 2009

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a b s t r a c tWe studied the effect of high-fat diet on the expression and activation of the three caveolins in rat skeletal muscle and their association with the insulin signalling cascade. Initial response was characterized by increased signalling through Cav-1 and Cav-3 phosphorylation, suggesting that both participate in an initial acute response to the calorie surplus. Afterwards, Cav-1 signalling was slightly reduced, whereas Cav-3 remained active. Late chronic phase signalling through both proteins was impaired inducing a prediabetic state. Summarizing, caveolins seem to mediate a timedependent regulation of insulin cascade in response to high-fat diet in muscle.

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Caveolin Is an Activator of Insulin Receptor Signaling

Cited by 270 publications

References 42 publications

Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance

Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance

Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

Time‐dependent regulation of muscle caveolin activation and insulin signalling in response to high‐fat diet

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