Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production, Leading to Improved Insulin Sensitivity.
Wei YingSumana MahataGautam K BandyopadhyayZhenqi ZhouJoshua WollamJessica VuRafael MayoralNai-Wen ChiNicholas J G WebsterAngelo CortiSushil K MahataPublished in: Diabetes (2018)
The activation of Kupffer cells (KCs) and monocyte-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Mice with diet-induced obesity (DIO mice) treated with chromogranin A peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of proinflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very proinflammatory in CST-KO NCD mice and produced glucose intolerance, we tested the effects of (sorted with FACS) F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal HGP and glucagon-induced HGP were markedly increased in hepatocytes cocultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pretreatment of CST-KO macrophages with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function.
Keyphrases
- high fat diet induced
- type diabetes
- insulin resistance
- blood glucose
- glycemic control
- induced apoptosis
- weight loss
- adipose tissue
- poor prognosis
- metabolic syndrome
- high glucose
- high fat diet
- cell cycle arrest
- skeletal muscle
- diabetic rats
- drug induced
- genome wide
- endothelial cells
- oxidative stress
- cardiovascular disease
- wild type
- blood pressure
- liver injury
- signaling pathway
- anti inflammatory
- long non coding rna
- cell death
- dna methylation
- body mass index
- fatty acid
- replacement therapy
- genome wide identification
- bioinformatics analysis
- risk assessment
- physical activity
- genome wide analysis
- climate change