Metformin attenuates insulin resistance by activating hypothalamic MC4R in high-fat diet-fed rats
10.3969/j.issn.1000-4718.2025.08.002
- VernacularTitle:二甲双胍通过激活下丘脑MC4R缓解高脂饮食大鼠胰岛素抵抗
- Author:
Yan LI
1
;
Haohao ZHANG
;
Yanqi REN
;
Lihui FENG
;
Youqin WANG
;
Lu ZHENG
Author Information
1. 长治医学院附属和平医院内分泌科,山西 长治 046000;长治医学院第一临床学院,山西 长治 046000
- Publication Type:Journal Article
- Keywords:
metformin;
melanocortin 4 receptor;
AMPK/SIRT1 signaling pathway;
insulin resistance
- From:
Chinese Journal of Pathophysiology
2025;41(8):1467-1476
- CountryChina
- Language:Chinese
-
Abstract:
AIM:To explore the central mechanisms by which metformin(Met)attenuates insulin resistance in high-fat diet(HF)-fed rats.METHODS:Forty healthy male Sprague-Dawley rats were randomly divided into 4 groups:normal chow(NC)group,HF group,HF+Met group,and HF+Met+SHU9119[melanocortin 4 receptor(MC4R)antagonist]group,with 10 rats per group.Treatments with HF and Met lasted for 12 weeks,while SHU9119 was injected for the last 10 d.Skeletal muscle AMP-activated protein kinase(AMPK)and silent information regulator 1(SIRT1)ex-pression and activity were measured,along with mitochondria oxidative stress markers,mitochondrial function and quanti-ty.Systemic and skeletal muscle insulin sensitivity were assessed using the average glucose infusion rate from 60 to 120 min(GIR60-120)and 2-deoxyglucose uptake(DGU)during hyperinsulinemic-euglycemic clamp.RESULTS:The rats in HF group exhibited significantly reduced expression and activity of AMPK/SIRT1 in skeletal muscles(P<0.05).More-over,mitochondrial oxidative stress markers,reactive oxygen species(ROS)and malondialdehyde(MDA),were marked-ly elevated(P<0.05),and the activity of antioxidant enzymes glutathione peroxidase(GPX)and manganese superoxide dismutase(MnSOD)was significantly decreased in HF group(P<0.05).There was also a notable decline in the activity of citrate synthase(P<0.05),a marker of mitochondrial oxidative capacity,and the copy number of mitochondrial DNA in HF group.These changes were correlated with significantly decreased GIR60-120 and DGU(P<0.05).Notably,Met treat-ment(HF+Met)restored the AMPK/SIRT1 expression and activity,improved mitochondrial function,and reduced oxida-tive stress,leading to improved insulin sensitivity(P<0.05).However,these beneficial effects of Met were reversed by the MC4R antagonist SHU9119 in HF+Met+SHU9119 group.CONCLUSION:Treatment with Met enhances skeletal muscle AMPK/SIRT1 expression and activity,reverses mitochondrial dysfunction,and improves insulin resistance in HF-fed rats.These effects might be mediated through the activation of hypothalamic MC4R.
