Fat Cell-Specific Ablation of Rictor in Mice Impairs Insulin-Regulated Fat Cell and Whole-Body Glucose and Lipid Metabolism

In a short-term (eight days) double-blind crossover study involving 10 obese patients, the effects of dexfenfluramine on glucose and lipid metabolism were examined. The protocol comprised whole body in vivo measurements (hyperinsulinemic euglycemic clamp in combination with indirect calorimetry) and in vitro studies of isolated adipocytes (lipolysis and glucose transport). All study participants were weight stable during the study period (103.1±3.2, placebo vs 103.3±3.1 kg, dexfenfluramine, NS). The following parameters were significantly reduced after dexfenfluramine treatment: fasting levels of plasma glucose (6.2±0.2 vs 5.7±0.2 mmol/l, p<0.01), serum insulin (168.0±14.5 vs 138.9±7.9 pmol/l, p<0.05), serum C-peptide (0.68±0.03 vs 0.58±0.02 nmol/l, p<0.05) and total serum cholesterol (6.07±0.41 vs 5.48±0.38 mmol/l, p< 0.01). In the basal state glucose oxidation rate was significantly reduced by 36% (p<0.001), whereas non-oxidative glucose disposal was significantly increased by 41% (p<0.01), following dexfenfluramine treatment. Insulin-stimulated (2 mU·kg−1·min−1) glucose disposal rate tended to be increased (18%, p=0.10) after dexfenfluramine. In conclusion, dexfenfluramine possesses beneficial regulatory effects on glucose and lipid metabolism in non-diabetic obese patients, independently of weight loss.

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A Discussion on the Relationship between Skin Lipid Metabolism and Whole-Body Glucose and Lipid Metabolism: Systematic Review

Journal of Cell Signaling ◽

10.4172/2576-1471.1000189 ◽

2018 ◽

Vol 03 (03) ◽

Author(s):

Sabrina N Dumas ◽

James M Ntambi

Keyword(s):

Systematic Review ◽

Lipid Metabolism ◽

Whole Body ◽

Skin Lipid ◽

Glucose And Lipid Metabolism ◽

The Relationship

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Effects of chronic hyperinsulinemia on metabolic pathways and insulin signaling in the fetal liver

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00323.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. E721-E733

Author(s):

Paul J. Rozance ◽

Amanda K. Jones ◽

Stephanie L. Bourque ◽

Angelo D’Alessandro ◽

William. W. Hay ◽

...

Keyword(s):

Lipid Metabolism ◽

Amino Acid ◽

Insulin Signaling ◽

Carbon Metabolism ◽

Fetal Liver ◽

Whole Body ◽

Ampk Activation ◽

Fetal Sheep ◽

Glucose And Lipid Metabolism ◽

One Carbon Metabolism

The effect of chronic of hyperinsulinemia in the fetal liver is poorly understood. Here, we produced hyperinsulinemia with euglycemia for ∼8 days in fetal sheep [hyperinsulinemic (INS)] at 0.9 gestation. INS fetuses had increased insulin and decreased oxygen and amino acid (AA) concentrations compared with saline-infused fetuses [control (CON)]. Glucose (whole body) utilization rates were increased, as expected, in INS fetuses. In the liver, however, there were few differences in genes and metabolites related to glucose and lipid metabolism and no activation of insulin signaling proteins (Akt and mTOR). There was increased p-AMPK activation and decreased mitochondrial mass ( PGC1A expression, mitochondrial DNA content) in INS livers. Using an unbiased multivariate analysis with 162 metabolites, we identified effects on AA and one-carbon metabolism in the INS liver. Expression of the transaminase BCAT2 and glutaminase genes GLS1 and GLS2 was decreased, supporting decreased AA utilization. We further evaluated the roles of hyperinsulinemia and hypoxemia, both present in INS fetuses, on outcomes in the liver. Expression of PGC1A correlated only with hyperinsulinemia, p-AMPK correlated only with hypoxemia, and other genes and metabolites correlated with both hyperinsulinemia and hypoxemia. In fetal hepatocytes, acute treatment with insulin activated p-Akt and decreased PGC1A, whereas hypoxia activated p-AMPK. Overall, chronic hyperinsulinemia produced greater effects on amino acid metabolism compared with glucose and lipid metabolism and a novel effect on one-carbon metabolism in the fetal liver. These hepatic metabolic responses may result from the downregulation of insulin signaling and antagonistic effects of hypoxemia-induced AMPK activation that develop with chronic hyperinsulinemia.

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NAD+-dependent deacetylase SIRT3 in adipocytes is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00057.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. E520-E530 ◽

Cited By ~ 7

Author(s):

Lane C. Porter ◽

Michael P. Franczyk ◽

Terri Pietka ◽

Shintaro Yamaguchi ◽

Jonathan B. Lin ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Whole Body ◽

Metabolic Complications ◽

Glucose And Lipid Metabolism ◽

Brown Adipose ◽

Gene And Protein Expression ◽

Whole Body Metabolism

Mitochondrial dysfunction in adipose tissue is involved in the pathophysiology of obesity-induced systemic metabolic complications, such as type 2 diabetes, insulin resistance, and dyslipidemia. However, the mechanisms responsible for obesity-induced adipose tissue mitochondrial dysfunction are not clear. The aim of present study was to test the hypothesis that nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin-3 (SIRT3) in adipocytes plays a critical role in adipose tissue mitochondrial biology and obesity. We first measured adipose tissue SIRT3 expression in obese and lean mice. Next, adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice were generated and metabolically characterized. We evaluated glucose and lipid metabolism in adult mice fed either a regular-chow diet or high-fat diet (HFD) and in aged mice. We also determined the effects of Sirt3 deletion on adipose tissue metabolism and mitochondrial biology. Supporting our hypothesis, obese mice had decreased SIRT3 gene and protein expression in adipose tissue. However, despite successful knockout of SIRT3, AMiSKO mice had normal glucose and lipid metabolism and did not change metabolic responses to HFD-feeding and aging. In addition, loss of SIRT3 had no major impact on putative SIRT3 targets, key metabolic pathways, and mitochondrial function in white and brown adipose tissue. Collectively, these findings suggest that adipocyte SIRT3 is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Contrary to our hypothesis, loss of SIRT3 function in adipocytes is unlikely to contribute to the pathophysiology of obesity-induced metabolic complications.

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Removal of Epididymal Visceral Adipose Tissue Prevents Obesity-Induced Multi-organ Insulin Resistance in Male Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab024 ◽

2021 ◽

Vol 5 (5) ◽

Author(s):

Michael P Franczyk ◽

Mai He ◽

Jun Yoshino

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Lipid Metabolism ◽

Visceral Adipose Tissue ◽

Body Weight Gain ◽

Whole Body ◽

Atherogenic Dyslipidemia ◽

Glucose And Lipid Metabolism ◽

Visceral Adipose

Abstract Obesity is associated with insulin resistance, an important risk factor of type 2 diabetes, atherogenic dyslipidemia, and nonalcoholic fatty liver disease. The major purpose of this study was to test hypothesize that prophylactic removal of epididymal visceral adipose tissue (VAT) prevents obesity-induced multi-organ (liver, skeletal muscle, adipose tissue) insulin resistance. Accordingly, we surgically removed epididymal VAT pads from adult C57BL/6J mice and evaluated in vivo and cellular metabolic pathways involved in glucose and lipid metabolism following chronic high-fat diet (HFD) feeding. We found that VAT removal decreases HFD-induced body weight gain while increasing subcutaneous adipose tissue (SAT) mass. Strikingly, VAT removal prevents obesity-induced insulin resistance and hyperinsulinemia and markedly enhances insulin-stimulated AKT-phosphorylation at serine-473 (Ser473) and threonine-308 (Thr308) sites in SAT, liver, and skeletal muscle. VAT removal leads to decreases in plasma lipid concentrations and hepatic triglyceride (TG) content. In addition, VAT removal increases circulating adiponectin, a key insulin-sensitizing adipokine, whereas it decreases circulating interleukin 6, a pro-inflammatory adipokine. Consistent with these findings, VAT removal increases adenosine monophosphate–activated protein kinase C phosphorylation, a major downstream target of adiponectin signaling. Data obtained from RNA sequencing suggest that VAT removal prevents obesity-induced oxidative stress and inflammation in liver and SAT, respectively. Taken together, these findings highlight the metabolic benefits and possible action mechanisms of prophylactic VAT removal on obesity-induced insulin resistance and hepatosteatosis. Our results also provide important insight into understanding the extraordinary capability of adipose tissue to influence whole-body glucose and lipid metabolism as an active endocrine organ.

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Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21

Journal of Endocrinology ◽

10.1530/joe-15-0136 ◽

2015 ◽

Vol 226 (3) ◽

pp. 207-217 ◽

Cited By ~ 24

Author(s):

João Paulo G Camporez ◽

Mohamed Asrih ◽

Dongyan Zhang ◽

Mario Kahn ◽

Varman T Samuel ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Whole Body ◽

Fibroblast Growth Factor 21 ◽

Glucose And Lipid Metabolism ◽

Hepatic Glucose

Fibroblast growth factor 21 (FGF21) is an important regulator of hepatic glucose and lipid metabolism and represents a potential pharmacological agent for the treatment of type 2 diabetes and obesity. Mice fed a ketogenic diet (KD) develop hepatic insulin resistance in association with high levels of FGF21, suggesting a state of FGF21 resistance. To address the role of FGF21 in hepatic insulin resistance, we assessed insulin action in FGF21 whole-body knock-out (FGF21 KO) male mice and their littermate WT controls fed a KD. Here, we report that FGF21 KO mice have hepatic insulin resistance and increased hepatic glucose production associated with an increase in plasma glucagon levels. FGF21 KO mice are also hypometabolic and display increased fat mass compared with their WT littermates. Taken together, these findings support a major role of FGF21 in regulating energy expenditure and hepatic glucose and lipid metabolism, and its potential role as a candidate in the treatment of diseases associated with insulin resistance.

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Alterations in basal nutrient metabolism increase resting energy expenditure in sickle cell disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.2.e357 ◽

1998 ◽

Vol 274 (2) ◽

pp. E357-E364 ◽

Cited By ~ 6

Author(s):

Myfanwy J. Borel ◽

Maciej S. Buchowski ◽

Ernest A. Turner ◽

Benjamin B. Peeler ◽

Richard E. Goldstein ◽

...

Keyword(s):

African American ◽

Lipid Metabolism ◽

Sickle Cell Disease ◽

Energy Expenditure ◽

Resting Energy Expenditure ◽

Whole Body ◽

Protein Breakdown ◽

Cell Disease ◽

Body Protein ◽

Glucose And Lipid Metabolism

Basal rates of whole body protein, glucose, and lipid metabolism and resting energy expenditure (REE) were measured in eight African-American sickle cell disease (SCD) patients and in six African-American controls. Catheters were placed 1) in an antecubital vein for stable isotope infusion and 2) in a heated hand vein for arterialized venous blood. Breath and blood were collected during the last 30 min of the 2.5-h study, and REE was measured by indirect calorimetry. REE [128 ± 5 vs. 111 ± 1 kJ ⋅ kg fat-free mass (FFM)−1 ⋅ day−1; P < 0.05 vs. controls] was 15% greater in the SCD patients. Whole body protein breakdown (5.0 ± 0.3 vs. 3.8 ± 0.2 mg ⋅ kg FFM−1 ⋅ min−1; P < 0.05 vs. controls) and protein synthesis (4.4 ± 0.3 vs. 3.2 ± 0.2 mg ⋅ kg FFM−1 ⋅ min−1; P< 0.05 vs. controls) were 32 and 38% greater, respectively, in the SCD patients, but whole body amino acid oxidation was similar (0.58 ± 0.03 vs. 0.66 ± 0.03 mg ⋅ kg FFM−1 ⋅ min−1). Measures of whole body glucose and lipid metabolism were not significantly different between the groups. The additional energy required for the greater rates of whole body protein breakdown and synthesis caused by SCD contributes significantly to the observed increase in REE, suggesting that dietary energy and protein requirements are enhanced in SCD patients.

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