Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance

Abstract

ObjectiveThe peptide hormone adropin regulates fuel selection preferences in skeletal muscle under fed and fasted conditions. Here, we investigated whether adropin treatment can ameliorate the dysregulation of fuel substrate metabolism, and improve aspects of glucose homeostasis in diet-induced obesity (DIO) with insulin resistance.MethodsDIO C57BL/6 mice maintained on a 60% kcal fat diet received five intraperitoneal (i.p.) injections of the bioactive peptide adropin34-76 (450 nmol/kg/i.p.). Following treatment, glucose tolerance and whole body insulin sensitivity were assessed and indirect calorimetry was employed to analyze whole body substrate oxidation preferences. Biochemical assays performed in skeletal muscle samples analyzed insulin signaling action and substrate oxidation.ResultsAdropin treatment improved glucose tolerance, enhanced insulin action and augmented metabolic flexibility towards glucose utilization. In muscle, adropin treatment increased insulin-induced Akt phosphorylation and cell-surface expression of GLUT4 suggesting sensitization of insulin signaling pathways. Reduced incomplete fatty acid oxidation and increased CoA/acetyl-CoA ratio suggested improved mitochondrial function. The underlying mechanisms appear to involve suppressions of carnitine palmitoyltransferase-1B (CPT-1B) and CD36, two key enzymes in fatty acid utilization. Adropin treatment activated pyruvate dehydrogenase (PDH), a rate-limiting enzyme in glucose oxidation, and downregulated PDH kinase-4 (PDK-4) that inhibits PDH. Along with these changes, adropin treatment downregulated peroxisome proliferator-activated receptor-gamma coactivator-1α that regulates expression of Cpt1b, Cd36 and Pdk4.ConclusionsAdropin treatment of DIO mice enhances glucose tolerance, ameliorates insulin resistance and promotes preferential use of carbohydrate over fat in fuel selection. Skeletal muscle is a key organ in mediating adropin's whole-body effects, sensitizing insulin signaling pathways and altering fuel selection preference to favor glucose while suppressing fat oxidation.

Serum Adropin and Adipose Fatty-Acid Binding Protein at 6th Week of Pregnancy Are Significant Predictors for Development of Insulin Resistance at the 24th Week.

“…However, against these data Gao et al (48) tried ADR treatment of diet-induced obesity with IR mice and found ADR treatment enhanced glucose tolerance, ameliorates IR and promotes preferential use of carbohydrate over fat in fuel selection and indicated a negative relationship between ADR level and high blood glucose level and IR; thus supporting the findings of the current study. Thereafter, Tuna et al (15) experimentally detected high serum ADR levels among animals received calorie-restricted diet, while was significantly lower among animals maintained on normal calorie intake, thus supporting the inverse correlation between serum ADR levels and calorie intake.…”

First and third trimester serum concentrations of adropin and copeptin in gestational diabetes mellitus and normal pregnancy

“…Moreover, increased release of adropin is related to the fed state and increased glucose oxidation by pyruvate dehydrogenase (PDH) complex activation. Furthermore, adropin inhibits carnitine palmitoyltransferase-1B (CPT1B), which reduces fatty acid oxidation (FAO) in muscles [17]. According to recent studies, it can be speculated that higher concentration of adropin in women with GDM is one of the multiple adaptive responses on adverse glucose metabolism during pregnancy.…”

Differential circulating concentrations of adipokines, glucagon and adropin in a clinical population of lean, overweight and diabetic cats

“…For example, adropin, a relatively newly discovered peptide hormone, is synthesized and secreted primarily by the liver but is also found in the heart and brain [9]. Dietary macronutrients stimulate adropin secretion and systemic injections of adropin to obese mice have been shown to improve glucose tolerance, skeletal muscle insulin sensitivity and promote weight loss [9, 29]. The role of adropin in the pathophysiology of feline obesity and diabetes is unknown.…”