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Leptin treatment inhibits the progression of atherosclerosis by attenuating hypercholesterolemia in type 1 diabetic Ins2(+/Akita):apoE(-/-) mice.

ABSTRACT: The impact of leptin deficiency and its replacement in T1D remain unclear in the context of dyslipidemia and atherosclerosis. The current study has investigated the physiologic role of leptin in lipid metabolism and atherosclerosis in T1D.The present study has employed Ins2(+/Akita):apoE(-/-) mouse model that spontaneously develops T1D, hypercholesterolemia, and atherosclerosis. At age 13 weeks, diabetic Ins2(+/Akita):apoE(-/-) mice showed leptin deficiency by ~92% compared with nondiabetic Ins2(+/+):apoE(-/-) mice. From 13 weeks to 25 weeks of age, diabetic Ins2(+/Akita):apoE(-/-) mice were treated with low-dose leptin (at 0.4 ?g/g body weight daily). Leptin treatment diminished food intake by 22-27% in diabetic mice without affecting body weight and lean mass throughout the experiment. Importantly, leptin therapy substantially reduced plasma cholesterol concentrations by ~41%, especially in LDL fractions, in diabetic Ins2(+/Akita):apoE(-/-) mice. Moreover, leptin therapy decreased atherosclerotic lesion in diabetic mice by ~62% comparable to that seen in nondiabetic mice. In addition, leptin restored repressed expression of hepatic sortilin-1, a receptor for LDL clearance, and reversed altered expression of several hepatic genes involved in lipogenesis and cholesterol synthesis characteristic of diabetic mice. These findings were accompanied by normalization of reduced hepatic expression of Irs1 and Irs2 mRNA as well as their protein levels, and improved hepatic insulin-receptor signaling.The present findings suggest that leptin administration may be useful to improve dyslipidemia and reduce atherosclerosis-related cardiovascular disease in human subjects with T1D.

SUBMITTER: Jun JY

PROVIDER: S-EPMC3502687 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Leptin treatment inhibits the progression of atherosclerosis by attenuating hypercholesterolemia in type 1 diabetic Ins2(+/Akita):apoE(-/-) mice.

Jun John Y JY Ma Zhexi Z Pyla Rajkumar R Segar Lakshman L

Atherosclerosis 20121012 2

<h4>Aims</h4>The impact of leptin deficiency and its replacement in T1D remain unclear in the context of dyslipidemia and atherosclerosis. The current study has investigated the physiologic role of leptin in lipid metabolism and atherosclerosis in T1D.<h4>Methods and results</h4>The present study has employed Ins2(+/Akita):apoE(-/-) mouse model that spontaneously develops T1D, hypercholesterolemia, and atherosclerosis. At age 13 weeks, diabetic Ins2(+/Akita):apoE(-/-) mice showed leptin deficien ...[more]

PMID: 23099119

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Project description:ObjectiveThe dominant-negative P467L mutation in peroxisome proliferator activated receptor-? (PPAR?) was identified in insulin-resistant patients with hyperglycemia and lipodystrophy. In contrast, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. We hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, which is masked by hyperinsulinemia and increased pancreatic islet mass, to retain normal plasma glucose.Research design and methodsWe introduced in Pparg(P465L/+) mice an Ins2-Akita mutation that causes improper protein folding and islet apoptosis to lower plasma insulin.ResultsUnlike Ins2(Akita/+) littermates, male Pparg(P465L/+)Ins2(Akita/+) mice have drastically reduced life span with enhanced type 1 diabetes. Hyperglycemia in Ins2(Akita/+) females is mild. However, Pparg(P465L/+)Ins2(Akita/+) females have aggravated hyperglycemia, smaller islets, and reduced plasma insulin. In an insulin tolerance test, they showed smaller reduction in plasma glucose, indicating impaired insulin sensitivity. Although gluconeogenesis is enhanced in Pparg(P465L/+)Ins2(Akita/+) mice compared with Ins2(Akita/+), exogenous insulin equally suppressed gluconeogenesis in hepatocytes, suggesting that Pparg(P465L/+)Ins2(Akita/+) livers are insulin sensitive. Expression of genes regulating insulin sensitivity and glycogen and triglyceride contents suggest that skeletal muscles are equally insulin sensitive. In contrast, adipose tissue and isolated adipocytes from Pparg(P465L/+)Ins2(Akita/+) mice have impaired glucose uptake in response to exogenous insulin. Pparg(P465L/+)Ins2(Akita/+) mice have smaller fat depots composed of larger adipocytes, suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia.ConclusionsPPARg-P465L mutation worsens hyperglycemia in Ins2(Akita/+) mice primarily because of adipose-specific insulin resistance and altered storage function. This underscores the important interplay between insulin and PPAR? in adipose tissues in diabetes.

Project description:ObjectiveHyperleptinemia, hallmark of obesity, is a putative pathophysiologic trigger for atherosclerosis. We previously reported a stimulatory effect of leptin on TSP-1 (thrombospondin-1) expression, a proatherogenic matricellular protein implicated in atherogenesis. However, a causal role of TSP-1 in leptin-driven atherosclerosis remains unknown. Approach and Results: Seventeen-weeks-old ApoE-/- and TSP-1-/-/ApoE-/- double knockout mice, on normocholesterolemic diet, were treated with or without murine recombinant leptin (5 µg/g bwt, IP) once daily for 3 weeks. Using aortic root morphometry and en face lesion assay, we found that TSP-1 deletion abrogated leptin-stimulated lipid-filled lesion burden, plaque area, and collagen accumulation in aortic roots of ApoE-/- mice, shown via Oil red O, hematoxylin and eosin, and Masson trichrome staining, respectively. Immunofluorescence microscopy of aortic roots showed that TSP-1 deficiency blocked leptin-induced inflammatory and smooth muscle cell abundance as well as cellular proliferation in ApoE-/- mice. Moreover, these effects were concomitant to changes in VLDL (very low-density lipoprotein)-triglyceride and HDL (high-density lipoprotein)-cholesterol levels. Immunoblotting further revealed reduced vimentin and pCREB (phospho-cyclic AMP response element-binding protein) accompanied with augmented smooth muscle-myosin heavy chain expression in aortic vessels of leptin-treated double knockout versus leptin-treated ApoE-/-; also confirmed in aortic smooth muscle cells from the mice genotypes, incubated ± leptin in vitro. Finally, TSP-1 deletion impeded plaque burden in leptin-treated ApoE-/- on western diet, independent of plasma lipid alterations.ConclusionsThe present study provides evidence for a protective effect of TSP-1 deletion on leptin-stimulated atherogenesis. Our findings suggest a regulatory role of TSP-1 on leptin-induced vascular smooth muscle cell phenotypic transition and inflammatory lesion invasion. Collectively, these results underscore TSP-1 as a potential target of leptin-induced vasculopathy.

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Leptin treatment inhibits the progression of atherosclerosis by attenuating hypercholesterolemia in type 1 diabetic Ins2(+/Akita):apoE(-/-) mice.

Publications

Leptin treatment inhibits the progression of atherosclerosis by attenuating hypercholesterolemia in type 1 diabetic Ins2(+/Akita):apoE(-/-) mice.

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