Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term
Dionysios V Chartoumpekis1, Dushani L Palliyaguru1, Nobunao Wakabayashi1
1Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Abstract:
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a canonical regulator of cytoprotective gene expression, but evidence of its cross talk with other pathways, including metabolic ones, is ever increasing. Pharmacologic or systemic genetic activation of the Nrf2 pathway partially protects from obesity in mice and ameliorates fasting hyperglycemia in mice and humans. However, systemic Nrf2 deletion also protects from diet-induced obesity and insulin resistance in mice. To further investigate the effect of the disruption of Nrf2 on obesity in a tissue-specific manner, we focused on adipocytes and hepatocytes with targeted deletion of Nrf2. To this end, mice with cell-specific deletion of Nrf2 in adipocytes (ANKO) or hepatocytes (HeNKO) were fed a high-fat diet (HFD) for 6 mo and showed similar increases in body weight and body fat content. ANKO mice showed a partially deteriorated glucose tolerance, higher fasting glucose levels, and higher levels of cholesterol and nonesterified fatty acids compared with their Control counterparts. The HeNKO mice, though, had lower insulin levels and trended toward improved insulin sensitivity without having any difference in liver triglyceride accumulation. This study compared for the first time two conditional Nrf2 knockout models in adipocytes and in hepatocytes during HFD-induced obesity. None of these models could completely recapitulate the unexpected protection against obesity observed in the whole body Nrf2 knockout mice, but this study points out the differential roles that Nrf2 may play, beyond cytoprotection, in different target tissues and rather suggests systemic activation of the Nrf2 pathway as an effective means of prevention and treatment of obesity and type 2 diabetes.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway disruption in specific tissues did not fully replicate systemic protection against diet-induced obesity. Systemic Nrf2 activation may be key for obesity and type 2 diabetes treatment.
Area of Science:
- Metabolic regulation
- Cellular stress response
- Obesity research
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cytoprotective genes.
- Nrf2 signaling interacts with metabolic pathways, influencing obesity and hyperglycemia.
- Systemic Nrf2 activation protects against obesity, while systemic deletion also confers protection.
Purpose of the Study:
- To investigate the tissue-specific roles of Nrf2 in adipocytes and hepatocytes in diet-induced obesity.
- To compare the effects of targeted Nrf2 deletion in adipocytes (ANKO) versus hepatocytes (HeNKO) on metabolic parameters.
- To understand how cell-specific Nrf2 disruption impacts obesity and related metabolic dysfunctions.
Main Methods:
- Generation of adipocyte-specific (ANKO) and hepatocyte-specific (HeNKO) Nrf2 knockout mice.
- Feeding mice a high-fat diet (HFD) for 6 months to induce obesity.
- Assessment of body weight, body fat, glucose tolerance, insulin levels, insulin sensitivity, cholesterol, nonesterified fatty acids, and liver triglycerides.
Main Results:
- Both ANKO and HeNKO mice exhibited similar increases in body weight and fat content on HFD.
- ANKO mice displayed impaired glucose tolerance, elevated fasting glucose, cholesterol, and nonesterified fatty acids.
- HeNKO mice showed reduced insulin levels and a trend towards improved insulin sensitivity, with no change in liver triglycerides.
Conclusions:
- Tissue-specific Nrf2 deletion in adipocytes or hepatocytes does not fully replicate the protective effects of systemic Nrf2 knockout against obesity.
- Nrf2 plays differential roles in metabolic regulation within various tissues beyond its cytoprotective functions.
- Systemic activation of the Nrf2 pathway presents a promising strategy for preventing and treating obesity and type 2 diabetes.
Related Concept Videos
01:35Long-term Potentiation
01:25Long-term Potentiation
Hebbian LTP
LTP can occur when...
01:20Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion
01:24Obesity
00:52What is Metabolism?
01:05Long-term Depression