Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies

ObjectiveGPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans.MethodsBioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans.ResultsBioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased.ConclusionsOur results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women

Hippo kinases Mst1 and Mst2 maintain NK cell homeostasis by orchestrating metabolic state and transcriptional activity

Abstract Natural killer (NK) cells play a crucial role in immune response against viral infections and tumors. However, further investigation is needed to better understand the key molecules responsible for determining the fate and function of NK cells. In this study, we made an important discovery regarding the involvement of the Hippo kinases Mst1 and Mst2 as novel regulators in maintaining mouse NK cell homeostasis. The presence of high Mst1 and Mst2 (Mst1/2) activity in NK cells is essential for their proper development, survival and function in a canonical Hippo signaling independent mode. Mechanistically, Mst1/2 induce cellular quiescence by regulating the processes of proliferation and mitochondrial metabolism, thereby ensuring the development and survival of NK cells. Furthermore, Mst1/2 effectively sense IL-15 signaling and facilitate the activation of pSTAT3-TCF1, which contributes to NK cell homeostasis. Overall, our investigation highlights the crucial role of Mst1/2 as key regulators in metabolic reprogramming and transcriptional regulation for mouse NK cell survival and function, emphasizing the significance of cellular quiescence during NK cell development and functional maturation

Gut ghrelin regulates hepatic glucose production and insulin signaling via a gut-brain-liver pathway

Abstract Background Ghrelin modulates many physiological processes. However, the effects of intestinal ghrelin on hepatic glucose production (HGP) are still unclear. The current study was to explore the roles of intestinal ghrelin on glucose homeostasis and insulin signaling in the liver. Methods The system of intraduodenal infusion and intracerebral microinfusion into the nucleus of the solitary tract (NTS) in the normal chow-diet rats and pancreatic-euglycemic clamp procedure (PEC) combined with [3-3H] glucose as a tracer were used to analyze the effect of intestinal ghrelin. Intraduodenal co-infusion of ghrelin, tetracaine and Activated Protein Kinase (AMPK) activator (AICAR), or pharmacologic and molecular inhibitor of N-methyl-D-aspartate receptors within the dorsal vagal complex, or hepatic vagotomy in rats were used to explore the possible mechanism of the effect of intestinal ghrelin on HGP. Results Our results demonstrated that gut infusion of ghrelin inhibited duodenal AMP-dependent protein kinase (AMPK) signal pathways, increased HGP and expression of gluconeogenic enzymes, and decreased insulin signaling in the liver of the rat. Intraduodenal co-infusion of ghrelin receptor antagonist [D-Lys3]-GHRP-6 and AMPK agonist with ghrelin diminished gut ghrelin-induced increase in HGP and decrease in glucose infusion rate (GIR) and hepatic insulin signaling. The effects of gut ghrelin were also negated by co-infusion with tetracaine, or MK801, an N-methyl-D-aspartate (NMDA) receptor inhibitor, and adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shNR1) within the dorsal vagal complex, and hepatic vagotomy in rats. When ghrelin and lipids were co-infused into the duodenum, the roles of gut lipids in increasing the rate of glucose infusion (GIR) and lowering HGP were reversed. Conclusions The current study provided evidence that intestinal ghrelin has an effect on HGP and identified a neural glucoregulatory function of gut ghrelin signaling

Hedgehog interacting protein as a circulating biomarker in women with obesity: a cross-sectional study and intervention studies

AbstractBackground Although a study found a significant increase in serum hedgehog interacting protein (HHIP) concentrations in impaired fasting blood glucose, impaired glucose tolerance and newly diagnosed T2DM patients, the variation in circulating HHIP levels in obese individuals remains unknown.Patients and methods Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes and signal pathways. The study is comprised of a total of 452 young women, including 248 obese individuals and 204 controls. Circulating HHIP and Adipoq levels were determined with ELISA kits. Euglycemic–hyperinsulinemic clamps (EHC) and oral glucose tolerance test (OGTT) were conducted in every subject. 32 women were given metformin and 49 were given liraglutide treatment for 6 weeks. The study was registered with www.chictr.org.cn (ChiCTR2000032878 and ChiCTR1800019776).Results Obesity was significantly associated with the cAMP signal pathway, and HHIP was a secreted protein related to cAMP signalling, as determined by KEGG analysis. In this population-based cohort study, we found that the level of circulating HHIP was significantly elevated in obese women, and positively correlated with body mass index and blood glucose, blood lipid, insulin, homeostasis model assessment of insulin resistance, dehydroepiandrostenedione sulphate, and luteinizing hormone, while negatively correlated with M-value and Adipoq. Insulin resistance (IR) and ove™rweight/obesity were associated with the higher HHIP concentration. OGTT and EHC tests revealed that the levels of circulating HHIP were regulated by blood glucose but to a less extent by insulin. After therapy with metformin and liraglutide, circulating HHIP levels were decreased, whereas Adipoq levels increased significantly.Conclusions Our findings support HHIP as a potential biomarker for predicting obesity and IR. In addition, drugs targeting HHIP may be a new strategy to treat obesity