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Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance
Published on: February 17, 2023
Molecular mechanism of insulin resistance and obesity
Takashi Kadowaki1, Kazuo Hara, Toshimasa Yamauchi
1Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. kadowaki-3im@h.u-tokyo.ac.jp
Abstract:
Obesity and insulin resistance have been recognized as leading causes of major health issues. We have endeavored to depict the molecular mechanism of insulin resistance, focusing on the function of adipocyte. We have investigated a role of PPARgamma on the pathogenesis of Type II diabetes. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. Moreover, a Pro12Ala polymorphism in the human PPARgamma2 gene was associated with decreased risk of Type II diabetes in Japanese. Taken together with these results, PPARgamma is proved to be a thrifty gene mediating Type II diabetes. Pharmacological inhibitors of PPARgamma/RXR ameliorate high-fat diet-induced insulin resistance in animal models of Type II diabetes. We have performed a genome-wide scan of Japanese Type 2 diabetic families using affected sib pair analysis. Our genome scan reveals at least 9 chromosomal regions potentially harbor susceptibility genes of Type II diabetes in Japanese. Among these regions, 3q26-q28 appeared to be very attractive one, because of the gene encoding adiponectin, the expression of which we had found enhanced in insulin-sensitive PPARgamma-deficient mice. Indeed, the subjects with the G/G genotype of SNP276 in the adiponectin gene were at increased risk for Type II diabetes compared with those having the T/T genotype. The plasma adiponectin levels were lower in the subjects with the G allele, suggesting that genetically inherited decrease in adiponectin levels predispose subjects to insulin resistance and Type II diabetes. Our work also confirmed that replenishment of adiponectin represents a novel treatment strategy for insulin resistance and Type II diabetes using animal models. Further investigation will be needed to clarify how adiponectin exerts its effect and to discover the molecular target of therapies.
Insights
Peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin play key roles in type 2 diabetes. PPARγ deficiency protects against insulin resistance, while adiponectin gene variations impact diabetes risk, suggesting therapeutic potential.
Area of Science:
- Metabolic diseases
- Genetics
- Molecular biology
Background:
- Obesity and insulin resistance are major health concerns.
- Understanding the molecular mechanisms of insulin resistance is crucial for developing effective treatments.
- Peroxisome proliferator-activated receptor gamma (PPARγ) has been implicated in the pathogenesis of type 2 diabetes.
Purpose of the Study:
- To elucidate the role of PPARγ in insulin resistance and type 2 diabetes.
- To identify genetic susceptibility loci for type 2 diabetes in the Japanese population.
- To investigate the function of adiponectin in insulin resistance and type 2 diabetes.
Main Methods:
- Studied heterozygous PPARγ-deficient mice fed a high-fat diet.
- Analyzed Pro12Ala polymorphism in the human PPARγ2 gene.
- Conducted genome-wide scans in Japanese type 2 diabetic families using affected sib pair analysis.
- Investigated single nucleotide polymorphisms (SNPs) in the adiponectin gene.
- Utilized animal models to assess adiponectin replenishment therapy.
Main Results:
- PPARγ-deficient mice were protected from diet-induced insulin resistance.
- A specific PPARγ2 gene polymorphism (Pro12Ala) was associated with reduced type 2 diabetes risk in Japanese individuals.
- Genome-wide scan identified chromosomal regions linked to type 2 diabetes susceptibility.
- A polymorphism (G/G genotype at SNP276) in the adiponectin gene increased type 2 diabetes risk.
- Lower plasma adiponectin levels were observed in individuals with the risk-associated adiponectin genotype.
- Adiponectin replenishment ameliorated insulin resistance in animal models.
Conclusions:
- PPARγ acts as a 'thrifty gene' contributing to type 2 diabetes development.
- Adiponectin deficiency, potentially due to genetic factors, predisposes individuals to insulin resistance and type 2 diabetes.
- Adiponectin replenishment shows promise as a therapeutic strategy for insulin resistance and type 2 diabetes.
- Further research is needed to understand adiponectin's precise mechanisms and identify therapeutic targets.
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