Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice
Females are, in general, more insulin sensitive than males. To investigate whether this is a direct effect of sex-steroids (SS) in white adipose tissue (WAT), we developed a male mouse model overexpressing the aromatase enzyme, converting testosterone (T) to estradiol (E2), specifically in WAT (Ap2-arom mice). Adipose tissue E2 levels were increased while circulating SS levels were unaffected in male Ap2-arom mice. Importantly, male Ap2-arom mice were more insulin sensitive compared with WT mice and exhibited increased serum adiponectin levels and upregulated expression of Glut4 and Irs1 in WAT. The expression of markers o...
Source: AJP: Endocrinology and Metabolism - October 1, 2017 Category: Endocrinology Authors: Ohlsson, C., Hammarstedt, A., Vandenput, L., Saarinen, N., Ryberg, H., Windahl, S. H., Farman, H. H., Jansson, J.-O., Moverare-Skrtic, S., Smith, U., Zhang, F.-P., Poutanen, M., Hedjazifar, S., Sjögren, K. Tags: Research Article Source Type: research
Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice
Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80...
Source: AJP: Endocrinology and Metabolism - October 1, 2017 Category: Endocrinology Authors: Zimmers, T. A., Jin, X., Zhang, Z., Jiang, Y., Koniaris, L. G. Tags: Research Article Source Type: research
Factors regulating subcutaneous adipose tissue storage, fibrosis, and inflammation may underlie low fatty acid mobilization in insulin-sensitive obese adults
Although the rate of fatty acid release from adipose tissue into the systemic circulation is very high in most obese adults, some obese adults maintain relatively low rates of fatty acid release, which helps protect them against the development of systemic insulin resistance. The primary aim of this study was to identify factors in adipose tissue that may underlie low vs. high rates of fatty acid mobilization in a relatively homogeneous cohort of obese adults. We measured systemic fatty acid rate of appearance (FA Ra) via 13C-palmitate isotope dilution, and we obtained subcutaneous abdominal adipose tissue samples from 30 ...
Source: AJP: Endocrinology and Metabolism - October 1, 2017 Category: Endocrinology Authors: Van Pelt, D. W., Guth, L. M., Wang, A. Y., Horowitz, J. F. Tags: Research Article Source Type: research
Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism
Propionate, 3-hydroxypropionate (3HP), methylcitrate, related compounds, and ammonium accumulate in body fluids of patients with disorders of propionyl-CoA metabolism, such as propionic acidemia. Although liver transplantation alleviates hyperammonemia, high concentrations of propionate, 3HP, and methylcitrate persist in body fluids. We hypothesized that conserved metabolic perturbations occurring in transplanted patients result from the simultaneous presence of propionate and 3HP in body fluids. We investigated the inter-relations of propionate and 3HP metabolism in perfused livers from normal rats using metabolomic and s...
Source: AJP: Endocrinology and Metabolism - October 1, 2017 Category: Endocrinology Authors: Wilson, K. A., Han, Y., Zhang, M., Hess, J. P., Chapman, K. A., Cline, G. W., Tochtrop, G. P., Brunengraber, H., Zhang, G.-F. Tags: Research Article Source Type: research
Deletion of UCP1 enhances ex vivo aortic vasomotor function in female but not male mice despite similar susceptibility to metabolic dysfunction
Females are typically more insulin sensitive than males, which may be partly attributed to greater brown adipose tissue (BAT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that UCP1 deletion would abolish sex differences in insulin sensitivity and that whitening of thoracic periaortic BAT caused by UCP1 loss would be accompanied with impaired thoracic aortic function. Furthermore, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency-induced metabolic dysfunction was mediated by oxidative stress. Compared with males, female mice had lower HOMA- and AT-insulin...
Source: AJP: Endocrinology and Metabolism - October 1, 2017 Category: Endocrinology Authors: Winn, N. C., Grunewald, Z. I., Gastecki, M. L., Woodford, M. L., Welly, R. J., Clookey, S. L., Ball, J. R., Gaines, T. L., Karasseva, N. G., Kanaley, J. A., Sacks, H. S., Vieira-Potter, V. J., Padilla, J. Tags: Research Article Source Type: research
MiR-27b augments bone marrow progenitor cell survival via suppressing the mitochondrial apoptotic pathway in Type 2 diabetes
Bone marrow-derived progenitor cells (BMPCs) are potential candidates for autologous cell therapy in tissue repair and regeneration because of their high angiogenic potential. However, increased progenitor cell apoptosis in diabetes directly limits their success in the clinic. MicroRNAs are endogenous noncoding RNAs that regulate gene expression at the posttranscriptional level, but their roles in BMPC-mediated angiogenesis are incompletely understood. In the present study, we tested the hypothesis that the proangiogenic miR-27b inhibits BMPC apoptosis in Type 2 diabetes. Bone marrow-derived EPCs from adult male Type 2 dia...
Source: AJP: Endocrinology and Metabolism - October 1, 2017 Category: Endocrinology Authors: Li, H., Liu, J., Wang, Y., Fu, Z., Hüttemann, M., Monks, T. J., Chen, A. F., Wang, J.-M. Tags: Research Article Source Type: research
Maternal methyl donor and cofactor supplementation in late pregnancy increases {beta}-cell numbers at 16 days of life in growth-restricted twin lambs
Restricted growth before birth (IUGR) increases adult risk of Type 2 diabetes by impairing insulin sensitivity and secretion. Altered fetal one-carbon metabolism is implicated in developmental programming of adult health and disease by IUGR. Therefore, we evaluated effects of maternal dietary supplementation with methyl donors and cofactors (MMDS), designed to increase fetal supply, on insulin action in the spontaneously IUGR twin lamb. In vivo glucose-stimulated insulin secretion and insulin sensitivity were measured at days 12–14 in singleton controls (CON, n = 7 lambs from 7 ewes), twins (IUGR, n = 8 lambs from 8 ...
Source: AJP: Endocrinology and Metabolism - October 1, 2017 Category: Endocrinology Authors: Sulaiman, S. A., De Blasio, M. J., Harland, M. L., Gatford, K. L., Owens, J. A. Tags: Research Article Source Type: research
Effects of metformin on compensatory pancreatic {beta}-cell hyperplasia in mice fed a high-fat diet
In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication. An 8-wk treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 wk of HFD feeding was similar in mice treated with and those treated without metformin. Interestingly, metformin suppressed β-cell proliferation induced by 1 wk of HFD feeding without any changes in insulin resistance. Metformin d...
Source: AJP: Endocrinology and Metabolism - September 11, 2017 Category: Endocrinology Authors: Tajima, K., Shirakawa, J., Okuyama, T., Kyohara, M., Yamazaki, S., Togashi, Y., Terauchi, Y. Tags: Research Article Source Type: research
Incretin secretion in humans is under the influence of cannabinoid receptors
The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels. Since cannabinoid receptors (CBRs) are expressed on incretin-secreting cells in rodents, we hypothesized that endocannabinoids are involved in the regulation of incretin secretion. We compared plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses during oral glucose tolerance test (OGTT) in 20 lean and 20 obese participants from the Baltimore Longitudinal Study of Aging (BLSA). Next, we recruited 20 healthy men to...
Source: AJP: Endocrinology and Metabolism - September 11, 2017 Category: Endocrinology Authors: Chia, C. W., Carlson, O. D., Liu, D. D., Gonzalez-Mariscal, I., Santa-Cruz Calvo, S., Egan, J. M. Tags: Research Article Source Type: research
CNS {beta}3-adrenergic receptor activation regulates feeding behavior, white fat browning, and body weight
Pharmacological β3-adrenergic receptor (β3AR) activation leads to increased mitochondrial biogenesis and activity in white adipose tissue (WAT), a process commonly referred to as "browning", and transiently increased insulin release. These effects are associated with improved metabolic function and weight loss. It is assumed that this impact of β3AR agonists is mediated solely through activation of β3ARs in adipose tissue. However, β3ARs are also found in the brain, in areas such as the brain stem and the hypothalamus, which provide multisynaptic innervation to brown and white adipose depots. Thus,...
Source: AJP: Endocrinology and Metabolism - September 11, 2017 Category: Endocrinology Authors: Richard, J. E., Lopez-Ferreras, L., Chanclon, B., Eerola, K., Micallef, P., Skibicka, K. P., Wernstedt Asterholm, I. Tags: Research Article Source Type: research
Expression of microRNAs and target proteins in skeletal muscle of rats selectively bred for high and low running capacity
Impairments in mitochondrial function and substrate metabolism are implicated in the etiology of obesity and Type 2 diabetes. MicroRNAs (miRNAs) can degrade mRNA or repress protein translation and have been implicated in the development of such disorders. We used a contrasting rat model system of selectively bred high- (HCR) or low- (LCR) intrinsic running capacity with established differences in metabolic health to investigate the molecular mechanisms through which miRNAs regulate target proteins mediating mitochondrial function and substrate oxidation processes. Quantification of select miRNAs using the rat miFinder miRN...
Source: AJP: Endocrinology and Metabolism - September 1, 2017 Category: Endocrinology Authors: Pinto, S. K., Lamon, S., Stephenson, E. J., Kalanon, M., Mikovic, J., Koch, L. G., Britton, S. L., Hawley, J. A., Camera, D. M. Tags: Research Article Source Type: research
The bradykinin-cGMP-PKG pathway augments insulin sensitivity via upregulation of MAPK phosphatase-5 and inhibition of JNK
In this study, we investigated whether BK acts via the sGC-cGMP-PKG pathway to inhibit the negative effects of JNK on insulin signaling and glucose uptake in rat adipocytes. BK augmented cGMP concentrations. The BK-induced enhancement of insulin-stimulated glucose uptake was mimicked by the sGC activator YC-1 and a cell-permeable cGMP analog, CPT-cGMP, and inhibited by the sGC inhibitor ODQ and the PKG inhibitor KT 5823. Transfection of dominant-negative PKG reduced the BK augmentation of insulin-induced Akt phosphorylation. The activation of JNK and ERK1/2 by insulin was attenuated by BK, which was mediated by the sGC-cGM...
Source: AJP: Endocrinology and Metabolism - September 1, 2017 Category: Endocrinology Authors: Frigolet, M. E., Thomas, G., Beard, K., Lu, H., Liu, L., Fantus, I. G. Tags: Research Article Source Type: research
Functional high-intensity training improves pancreatic {beta}-cell function in adults with type 2 diabetes
We examined the effect of a novel, 6-wk CrossFit functional high-intensity training (F-HIT) intervention on β-cell function in 12 sedentary adults with clinically diagnosed T2D (54 ± 2 yr, 166 ± 16 mg/dl fasting glucose). Supervised training was completed 3 days/wk, comprising functional movements performed at a high intensity in a variety of 10- to 20-min sessions. All subjects completed an oral glucose tolerance test and anthropometric measures at baseline and following the intervention. The mean disposition index, a validated measure of β-cell function, was significantly increased (PRE: 8.4 &plus...
Source: AJP: Endocrinology and Metabolism - September 1, 2017 Category: Endocrinology Authors: Nieuwoudt, S., Fealy, C. E., Foucher, J. A., Scelsi, A. R., Malin, S. K., Pagadala, M., Rocco, M., Burguera, B., Kirwan, J. P. Tags: Research Article Source Type: research
Map4k4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity
The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesit...
Source: AJP: Endocrinology and Metabolism - September 1, 2017 Category: Endocrinology Authors: Roth Flach, R. J., DiStefano, M. T., Danai, L. V., Senol-Cosar, O., Yawe, J. C., Kelly, M., Garcia Menendez, L., Czech, M. P. Tags: Research Article Source Type: research
Fibroblast growth factor 21: a regulator of metabolic disease and health span
Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention for its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas, with profound effects and therapeutic relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21, which include, but are not limited to, weight loss, glucose and lipid metabolism, and insulin...
Source: AJP: Endocrinology and Metabolism - September 1, 2017 Category: Endocrinology Authors: Xie, T., Leung, P. S. Tags: Review Source Type: research
