Abstract
Aims/hypothesisIn the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.MethodsWe studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant’s effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.ResultsAcute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.Conclusions/interpretationWe conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.
Highlights
Type 2 diabetes is defined as a metabolic disorder characterised by systemic insulin resistance which results in hyperglycaemia
Based on the use of the new inducible fat-specific insulin receptor (IR) knockout (iFIRKO)-tracer mouse model, we conclude that the iFIRKO mouse model does not resemble the typical lipoatrophic mouse models such as the FAT-ATTAC [19] or the A-Zip/F-1 mouse models [20], which exhibit a loss of adipocytes and ectopic deposition of lipids
In iFIRKO mice there seems to be no full compensation for the reduction of adipocyte size and mass of the various adipose tissue depots, because they are protected from excessive weight gain when mice are fed an obesogenic diet after the induction of IR knockout
Summary
Type 2 diabetes is defined as a metabolic disorder characterised by systemic insulin resistance which results in hyperglycaemia. The tamoxifen-inducible fat-specific IR knockout (iFIRKO) mouse model established for the first time a causal relationship between insulin resistance in adipocytes and early stages of type 2 diabetes development [6]. Congenital leptin deficiency causes overeating which leads to obesity in early life in humans [9, 10], as well as in mice [11] Another factor reported to contribute to insulin resistance in the adipose tissue is oxidative stress [12,13,14]; this concept has been widely criticised for the lack of evidence and negative outcomes in both human correlative food supplementation studies and mouse experiments [15]
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