American journal of physiology. Endocrinology and metabolism
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Am. J. Physiol. Endocrinol. Metab. · Nov 2019
Micro-RNA-27a/b negatively regulates hepatic gluconeogenesis by targeting FOXO1.
In the context of hepatic insulin resistance, hepatic gluconeogenesis is abnormally increased, which results in increased hepatic glucose production and hyperglycemia, but the underlying mechanisms remain to be fully elucidated. Micro-RNAs (miRNAs) have been identified as critical regulators of diabetes and other metabolic disorders. In this study, we found that the expressions of miRNA-27 family members miRNA-27a and miRNA-27b (miR-27a/b) decreased significantly in the livers of diabetic mice. ⋯ Overexpression of miR-27a/b suppressed hepatic glucose output and alleviated hyperglycemia in diabetic mice. Further study revealed that forkhead box O1 (FOXO1) is a downstream target of miR-27a/b. Taken together, we found novel evidence suggesting that miR-27a/b contributes to hepatic gluconeogenesis through targeting FOXO1 and provided novel mechanistic insight into the pathophysiology of insulin resistance.
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Am. J. Physiol. Endocrinol. Metab. · Sep 2019
Comparative StudyA comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women.
Skeletal muscle mitochondrial respiration is thought to be altered in obesity, insulin resistance, and type 2 diabetes; however, the invasive nature of tissue biopsies is an important limiting factor for studying mitochondrial function. Recent findings suggest that bioenergetics profiling of circulating cells may inform on mitochondrial function in other tissues in lieu of biopsies. Thus, we sought to determine whether mitochondrial respiration in circulating cells [peripheral blood mononuclear cells (PBMCs) and platelets] reflects that of skeletal muscle fibers derived from the same subjects. ⋯ In a subset of samples (n = 12-13) with permeabilized blood cells available, raw measures of substrate (pyruvate, malate, glutamate, and succinate)-driven respiration did not correlate between permeabilized muscle (per mg tissue) and permeabilized PBMCs (per 106 cells); however, complex I leak and oxidative phosphorylation coupling efficiency correlated between permeabilized platelets and muscle (Spearman's ρ = 0.64, P = 0.030; Spearman's ρ = 0.72, P = 0.010, respectively). Our data indicate that bioenergetics phenotypes in circulating cells cannot recapitulate muscle mitochondrial function. Select circulating cell bioenergetics phenotypes may possibly inform on overall metabolic health, but this postulate awaits validation in cohorts spanning a larger range of insulin resistance and type 2 diabetes status.
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Am. J. Physiol. Endocrinol. Metab. · May 2019
Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans.
Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. ⋯ Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.
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Am. J. Physiol. Endocrinol. Metab. · Jul 2018
Low-dose brain estrogen prevents menopausal syndrome while maintaining the diversity of the gut microbiomes in estrogen-deficient rats.
We evaluated the effects of intracerebroventricular administration (ICV) of brain estrogen and progesterone on menopausal symptoms and their effects on the secretion of follicle-stimulating hormone(FSH) and luteinizing hormone (LH) in estrogen-deficient rats. Three weeks after ovariectomy (OVX) or sham operation, OVX rats were given ICV infusions of either 17β-estradiol (4 μg/day; ICV-E), progesterone(0.8 μg/day; ICV-P), or vehicle (control) for 4 wk. OVX rats in the positive-control group were orally provided 150 μg 17β-estradiol·kg body wt-1·day-1. ⋯ The control group exhibited decreased short-term memory and spatial memory compared with the other groups. Surprisingly, the control group exhibited a decreased richness of the gut microbiome compared with normal-control group, and ICV-E protected against the decrease the most. In conclusion, small amounts of brain estrogen and, to some extent, progesterone improved menopausal symptoms by decreasing serum FSH levels and maintaining the diversity of the gut microbiome in estrogen-deficient rats.
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Am. J. Physiol. Endocrinol. Metab. · Jun 2018
Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain.
Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. ⋯ On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose-induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding.