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SIRT2 knockout exacerbates insulin resistance in high fat-fed mice.
Lantier L, Williams AS, Hughey CC, Bracy DP, James FD, Ansari MA, Gius D, Wasserman DH
(2018) PLoS One 13: e0208634
MeSH Terms: Acetylation, Animals, Diet, High-Fat, Energy Metabolism, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Muscle, Skeletal, Phosphorylation, Proto-Oncogene Proteins c-akt, Sirtuin 2
Show Abstract · Added January 8, 2019
The NAD+-dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.
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16 MeSH Terms
Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.
Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR
(2019) Gastroenterology 156: 1041-1051.e4
MeSH Terms: Anastomosis, Surgical, Animals, Anticholesteremic Agents, Bariatric Surgery, Bile Acids and Salts, Blood Glucose, Cholestyramine Resin, Diet, High-Fat, Gallbladder, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose Tolerance Test, Ileum, Insulin Resistance, Intestines, Lymph, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Signal Transduction, Verrucomicrobia, Weight Loss
Show Abstract · Added January 4, 2019
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity.
McDonnell WJ, Koethe JR, Mallal SA, Pilkinton MA, Kirabo A, Ameka MK, Cottam MA, Hasty AH, Kennedy AJ
(2018) Diabetes 67: 2361-2376
MeSH Terms: Adipose Tissue, Animals, CD8-Positive T-Lymphocytes, Complementarity Determining Regions, Diet, High-Fat, Glucose Tolerance Test, Insulin Resistance, Liver, Male, Mice, Obesity, Prostaglandins
Show Abstract · Added March 26, 2019
Adipose tissue (AT) CD4 and CD8 T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8 and CD4 TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8 T cells, HFD reduced TCR diversity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8 T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice; isoLGs were elevated in M2-polarized macrophages, promoting CD8 T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.
© 2018 by the American Diabetes Association.
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MeSH Terms
Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes.
Li Z, Li Y, Overstreet JM, Chung S, Niu A, Fan X, Wang S, Wang Y, Zhang MZ, Harris RC
(2018) Diabetes 67: 1847-1857
MeSH Terms: Albuminuria, Animals, Biomarkers, Crosses, Genetic, Cytokines, Diabetes Mellitus, Type 2, Diabetic Nephropathies, ErbB Receptors, Erlotinib Hydrochloride, Fibrosis, Glomerulonephritis, Hypoglycemic Agents, Insulin Resistance, Kidney, Macrophages, Membrane Transport Modulators, Mice, Knockout, Mice, Mutant Strains, Nitric Oxide Synthase Type III, Oxidative Stress, Protein Kinase Inhibitors, T-Lymphocytes, Transforming Growth Factor alpha
Show Abstract · Added November 9, 2018
Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and that inhibition of EGFR activity protects against progressive DN in type 1 diabetes. In this study we examined whether inhibition of EGFR activation would affect the development of DN in a mouse model of accelerated type 2 diabetes (BKS with endothelial nitric oxide knockout [eNOS]). eNOS mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity, beginning at 8 weeks of age and were sacrificed at 20 weeks of age. In addition, genetic models inhibiting EGFR activity () and transforming growth factor-α () were studied in this model of DN in type 2 diabetes. Compared with vehicle-treated mice, erlotinib-treated animals had less albuminuria and glomerulosclerosis, less podocyte loss, and smaller amounts of renal profibrotic and fibrotic components. Erlotinib treatment decreased renal oxidative stress, macrophage and T-lymphocyte infiltration, and the production of proinflammatory cytokines. Erlotinib treatment also preserved pancreas function, and these mice had higher blood insulin levels at 20 weeks, decreased basal blood glucose levels, increased glucose tolerance and insulin sensitivity, and increased blood levels of adiponectin compared with vehicle-treated mice. Similar to the aforementioned results, both and diabetic mice also had attenuated DN, preserved pancreas function, and decreased basal blood glucose levels. In this mouse model of accelerated DN, inhibition of EGFR signaling led to increased longevity.
© 2018 by the American Diabetes Association.
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23 MeSH Terms
Acute effects of insulin on circulating natriuretic peptide levels in humans.
Bachmann KN, Deger SM, Alsouqi A, Huang S, Xu M, Ferguson JF, Su YR, Niswender KD, Ikizler TA, Wang TJ
(2018) PLoS One 13: e0196869
MeSH Terms: Adult, Aged, Atrial Natriuretic Factor, Female, Glucose Clamp Technique, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Natriuretic Peptide, Brain, Obesity, Peptide Fragments
Show Abstract · Added April 2, 2019
BACKGROUND - The natriuretic peptide hormones play an important role in salt and blood pressure regulation. In observational studies, obesity and insulin resistance have been consistently associated with lower concentrations of natriuretic peptides. It has been proposed that insulin influences natriuretic peptide production.
OBJECTIVE - We sought to determine the acute effects of insulin administration on natriuretic peptide concentrations.
METHODS - 31 men and women (11 lean, 10 overweight, and 10 obese), ages 30-70 years, without cardiovascular disease or overt diabetes underwent a hyperinsulinemic-euglycemic insulin clamp. Plasma concentrations of N-terminal pro atrial natriuretic peptide (NT-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured at baseline and steady-state (the final 30 minutes of the clamp protocol).
RESULTS - From baseline to steady-state, insulin levels increased from a mean level of 9.5 to 176.7 μU/ml (p<0.001). Over this period, circulating NT-proANP concentrations decreased by 9% (-1933 ng/L, p = 0.01). The changes in NT-proANP did not differ between lean, overweight, and obese individuals. Steady-state NT-proANP levels, adjusted for baseline, were lower in individuals with greater insulin resistance, independent of BMI. In contrast to NT-proANP, NT-proBNP levels did not change significantly during the clamp (p = 0.41).
CONCLUSION - Insulin administration was associated with a moderate decrease in circulating NT-proANP, but not NT-proBNP. The lowest NT-proANP concentrations were found in insulin-resistant individuals. Further investigations are warranted to elucidate potential mechanisms underlying the effects of insulin on the cardiac hormonal axis.
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MeSH Terms
Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.
Samovski D, Dhule P, Pietka T, Jacome-Sosa M, Penrose E, Son NH, Flynn CR, Shoghi KI, Hyrc KL, Goldberg IJ, Gamazon ER, Abumrad NA
(2018) Diabetes 67: 1272-1284
MeSH Terms: Animals, CD36 Antigens, CHO Cells, Carbohydrate Metabolism, Cells, Cultured, Cricetinae, Cricetulus, Diabetes Mellitus, Type 2, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Receptor, Insulin, Signal Transduction
Show Abstract · Added May 26, 2018
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
© 2018 by the American Diabetes Association.
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20 MeSH Terms
Balanced high fat diet reduces cardiovascular risk in obese women although changes in adipose tissue, lipoproteins, and insulin resistance differ by race.
Niswender KD, Fazio S, Gower BA, Silver HJ
(2018) Metabolism 82: 125-134
MeSH Terms: Adipose Tissue, Adult, African Continental Ancestry Group, Cardiovascular Diseases, Diet, High-Fat, European Continental Ancestry Group, Female, Humans, Insulin Resistance, Lipoproteins, Middle Aged, Obesity, Risk Factors, Young Adult
Show Abstract · Added April 10, 2018
BACKGROUND - We previously reported that consuming a balanced high fat diet (BHFD) wherein total saturated fat was reduced and total unsaturated fat increased by proportionately balancing the type of fat (1/3 saturated, 1/3 monounsaturated, 1/3 polyunsaturated) led to significant improvements in inflammatory burden, blood pressure, and vascular function in obese premenopausal European American (EA) and African American (AA) women.
OBJECTIVE - Here we compared changes in adipose tissue, lipoproteins, insulin resistance, and cardiovascular risk between EA and AA women.
METHODS - Dietary intakes, plasma fatty acids, lipids, apolipoproteins, lipoproteins, HOMA-IR and ASCVD risk was measured in 144 women who consumed BHFD for 16 weeks. Generalized linear modeling was performed while controlling for change in body weight.
RESULTS - EA women had greater reductions in visceral adipose tissue. Only EA women had significant reductions in fasting insulin levels (↓24.8%) and HOMA-IR (↓29%) scores. In EA women, the most significant improvements occurred in VLDL particle size (↑), apolipoprotein B levels (↑), serum TG (↓), number of plasma LDL particles (↓), and serum LDL-cholesterol (↓). In AA women, significant improvements occurred in HDL particle size (↑), number of large HDL particles (↑), and apolipoprotein AI levels (↑). Consequently, both groups had improved ASCVD risk scores (↓5.5%).
CONCLUSIONS - Consuming the balanced high fat diet led to significant reduction in cardiovascular risk factors in both groups. However, the pattern of response to BHFD differed with EA women responding more in components of the apolipoprotein B pathway versus AA women responding more in components of the apolipoprotein AI pathway.
Published by Elsevier Inc.
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14 MeSH Terms
Hepatocyte estrogen receptor alpha mediates estrogen action to promote reverse cholesterol transport during Western-type diet feeding.
Zhu L, Shi J, Luu TN, Neuman JC, Trefts E, Yu S, Palmisano BT, Wasserman DH, Linton MF, Stafford JM
(2018) Mol Metab 8: 106-116
MeSH Terms: Animals, Atherosclerosis, Biological Transport, Cells, Cultured, Cholesterol, Diet, Western, Estrogen Receptor alpha, Female, Hepatocytes, Insulin Resistance, Macrophages, Male, Mice, Mice, Inbred C57BL, Obesity, Sex Factors
Show Abstract · Added April 10, 2018
OBJECTIVE - Hepatocyte deletion of estrogen receptor alpha (LKO-ERα) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ERα regulates reverse cholesterol transport (RCT) in mice has not yet been reported.
METHODS AND RESULTS - Using LKO-ERα mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ERα impaired in vivo RCT measured by the removal of H-cholesterol from macrophages to the liver, and subsequently to feces, in female mice but not in male mice. Deletion of hepatocyte ERα decreased the capacity of isolated HDL to efflux cholesterol from macrophages and reduced the ability of isolated hepatocytes to accept cholesterol from HDL ex vivo in both sexes. However, only in female mice, LKO-ERα increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ERα increased adiposity and worsened insulin resistance to a greater degree in female than male mice. All of the changes lead to a 5.6-fold increase in the size of early atherosclerotic lesions in female LKO-ERα mice compared to WT controls.
CONCLUSIONS - Estrogen signaling through hepatocyte ERα plays an important role in RCT and is protective against lipid retention in the artery wall during early stages of atherosclerosis in female mice fed a Western-type diet.
Published by Elsevier GmbH.
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16 MeSH Terms
Pyruvate induces torpor in obese mice.
Soto M, Orliaguet L, Reyzer ML, Manier ML, Caprioli RM, Kahn CR
(2018) Proc Natl Acad Sci U S A 115: 810-815
MeSH Terms: Adenosine, Adipose Tissue, Brown, Animals, Brain, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Pyruvic Acid, Torpor, Uncoupling Protein 1
Show Abstract · Added March 22, 2018
Mice subjected to cold or caloric deprivation can reduce body temperature and metabolic rate and enter a state of torpor. Here we show that administration of pyruvate, an energy-rich metabolic intermediate, can induce torpor in mice with diet-induced or genetic obesity. This is associated with marked hypothermia, decreased activity, and decreased metabolic rate. The drop in body temperature correlates with the degree of obesity and is blunted by housing mice at thermoneutrality. Induction of torpor by pyruvate in obese mice relies on adenosine signaling and is accompanied by changes in brain levels of hexose bisphosphate and GABA as detected by mass spectroscopy-based imaging. Pyruvate does not induce torpor in lean mice but results in the activation of brown adipose tissue (BAT) with an increase in the level of uncoupling protein-1 (UCP1). Denervation of BAT in lean mice blocks this increase in UCP1 and allows the pyruvate-induced torpor phenotype. Thus, pyruvate administration induces torpor in obese mice by pathways involving adenosine and GABA signaling and a failure of normal activation of BAT.
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12 MeSH Terms
An insulin resistance associated neural correlate of impulsivity in type 2 diabetes mellitus.
Eckstrand KL, Mummareddy N, Kang H, Cowan R, Zhou M, Zald D, Silver HJ, Niswender KD, Avison MJ
(2017) PLoS One 12: e0189113
MeSH Terms: Adult, Corpus Striatum, Diabetes Mellitus, Type 2, Female, Humans, Impulsive Behavior, Insulin Resistance, Magnetic Resonance Imaging, Male, Middle Aged
Show Abstract · Added March 21, 2018
Central insulin resistance (IR) influences striatal dopamine (DA) tone, an important determinant of behavioral self-regulation. We hypothesized that an association exists between the degree of peripheral IR and impulse control, mediated by the impact of IR on brain circuits controlling the speed of executing "go" and/or "stop" responses. We measured brain activation and associated performance on a stop signal task (SST) in obese adults with type 2 diabetes (age, 48.1 ± 6.9 yrs (mean ± SD); BMI, 36.5 ± 4.0 kg/m2; HOMA-IR, 7.2 ± 4.1; 12 male, 18 female). Increasing IR, but not BMI, was a predictor of shorter critical stop signal delay (cSSD), a measure of the time window during which a go response can be successfully countermanded (R2 = 0.12). This decline was explained by an IR-associated increase in go speed (R2 = 0.13) with little impact of IR or BMI on stop speed. Greater striatal fMRI activation contrast in stop error (SE) compared with stop success (SS) trials (CONSE>SS) was a significant predictor of faster go speeds (R2 = 0.33, p = 0.002), and was itself predicted by greater IR (CONSE>SS vs HOMA-IR: R2 = 0.10, p = 0.04). Furthermore, this impact of IR on striatal activation was a significant mediator of the faster go speeds and greater impulsivity observed with greater IR. These findings suggest a neural mechanism by which IR may increase impulsivity and degrade behavioral self-regulation.
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10 MeSH Terms