Differential and synergistic effects of low birth weight and Western diet on skeletal muscle vasculature, mitochondrial lipid metabolism and insulin signaling in male guinea pigs

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar Western diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male lean offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism as reflected by in-creased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high fat-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism promoting mitochondrial overload.

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Differential and Synergistic Effects of Low Birth Weight and Western Diet on Skeletal Muscle Vasculature, Mitochondrial Lipid Metabolism and Insulin Signaling in Male Guinea Pigs

Nutrients ◽

10.3390/nu13124315 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4315

Author(s):

Kristyn Dunlop ◽

Ousseynou Sarr ◽

Nicole Stachura ◽

Lin Zhao ◽

Karen Nygard ◽

...

Keyword(s):

Skeletal Muscle ◽

Lipid Metabolism ◽

Birth Weight ◽

Amino Acid ◽

Low Birth Weight ◽

Insulin Signaling ◽

Western Diet ◽

High Fat ◽

High Sugar ◽

Mitochondrial Lipid

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar “Western” diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male “lean” offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload.

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Plasma amino acid levels are elevated in young, healthy low birth weight men exposed to short-term high-fat overfeeding

Physiological Reports ◽

10.14814/phy2.13044 ◽

2016 ◽

Vol 4 (23) ◽

pp. e13044 ◽

Cited By ~ 9

Author(s):

Amalie Ribel-Madsen ◽

Lars I. Hellgren ◽

Charlotte Brøns ◽

Rasmus Ribel-Madsen ◽

Christopher B. Newgard ◽

...

Keyword(s):

Birth Weight ◽

Amino Acid ◽

Low Birth Weight ◽

Plasma Amino Acid ◽

High Fat ◽

Short Term ◽

Amino Acid Levels

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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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High-Fat Overfeeding Impairs Peripheral Glucose Metabolism and Muscle Microvascular eNOS Ser1177 Phosphorylation

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz018 ◽

2019 ◽

Vol 105 (1) ◽

pp. 65-77 ◽

Cited By ~ 10

Author(s):

Siôn A Parry ◽

Mark C Turner ◽

Rachel M Woods ◽

Lewis J James ◽

Richard A Ferguson ◽

...

Keyword(s):

Skeletal Muscle ◽

Glycemic Control ◽

Insulin Signaling ◽

Dietary Fat ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Whole Body ◽

High Fat ◽

Before And After ◽

Protein Ingestion

Abstract Context The mechanisms responsible for dietary fat-induced insulin resistance of skeletal muscle and its microvasculature are only partially understood. Objective To determine the impact of high-fat overfeeding on postprandial glucose fluxes, muscle insulin signaling, and muscle microvascular endothelial nitric oxide synthase (eNOS) content and activation. Design Fifteen non-obese volunteers consumed a high-fat (64%) high-energy (+47%) diet for 7 days. Experiments were performed before and after the diet. Stable isotope tracers were used to determine glucose fluxes in response to carbohydrate plus protein ingestion. Muscle insulin signaling was determined as well as the content and activation state of muscle microvascular eNOS. Results High-fat overfeeding impaired postprandial glycemic control as demonstrated by higher concentrations of glucose (+11%; P = 0.004) and insulin (+19%; P = 0.035). Carbohydrate plus protein ingestion suppressed endogenous glucose production to a similar extent before and after the diet. Conversely, high-fat overfeeding reduced whole-body glucose clearance (–16%; P = 0.021) and peripheral insulin sensitivity (–26%; P = 0.006). This occurred despite only minor alterations in skeletal muscle insulin signaling. High-fat overfeeding reduced eNOS content in terminal arterioles (P = 0.017) and abolished the increase in eNOS Ser1177 phosphorylation that was seen after carbohydrate plus protein ingestion. Conclusion High-fat overfeeding impaired whole-body glycemic control due to reduced glucose clearance, not elevated endogenous glucose production. The finding that high-fat overfeeding abolished insulin-mediated eNOS Ser1177 phosphorylation in the terminal arterioles suggests that impairments in the vasodilatory capacity of the skeletal muscle microvasculature may contribute to early dietary fat-induced impairments in glycemic control.

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Transcript profile of skeletal muscle lipid metabolism genes affected by diet in a piglet model of low birth weight

PLoS ONE ◽

10.1371/journal.pone.0224484 ◽

2019 ◽

Vol 14 (10) ◽

pp. e0224484

Author(s):

Quentin L. Sciascia ◽

Gürbüz Daş ◽

Steffen Maak ◽

Claudia Kalbe ◽

Barbara U. Metzler-Zebeli ◽

...

Keyword(s):

Skeletal Muscle ◽

Lipid Metabolism ◽

Birth Weight ◽

Low Birth Weight ◽

Transcript Profile ◽

Muscle Lipid ◽

Skeletal Muscle Lipid ◽

Lipid Metabolism Genes

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Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90774.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. R243-R251 ◽

Cited By ~ 85

Author(s):

Kerry L. Mullen ◽

Janet Pritchard ◽

Ian Ritchie ◽

Laelie A. Snook ◽

Adrian Chabowski ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Lipid Metabolism ◽

Protein Kinase ◽

Glucose Transport ◽

Insulin Signaling ◽

Lipid Accumulation ◽

Time Course ◽

Protein Kinase B ◽

High Fat

High-fat (HF) diets can induce insulin resistance (IR) by altering skeletal muscle lipid metabolism. An imbalance between fatty acid (FA) uptake and oxidation results in intramuscular lipid accumulation, which can impair the insulin-signaling cascade. Adiponectin (Ad) is an insulin-sensitizing adipokine known to stimulate skeletal muscle FA oxidation and reduce lipid accumulation. Evidence of Ad resistance has been shown in obesity and following chronic HF feeding and may contribute to lipid accumulation observed in these conditions. Whether Ad resistance precedes and is associated with the development of IR is unknown. We conducted a time course HF feeding trial for 3 days, 2 wk, or 4 wk to determine the onset of Ad resistance and identify the ensuing changes in lipid metabolism and insulin signaling leading to IR in skeletal muscle. Ad stimulated FA oxidation (+28%, P ≤ 0.05) and acetyl-CoA carboxylase phosphorylation (+34%, P ≤ 0.05) in control animals but failed to do so in any HF-fed group (i.e., as early as 3 days). By 2 wk, plasma membrane FA transporters and intramuscular diacylglycerol (DAG) and ceramide were increased, and insulin-stimulated phosphorylation of both protein kinase B and protein kinase B substrate 160 was blunted compared with control animals. After 4 wk of HF feeding, maximal insulin-stimulated glucose transport was impaired compared with control. Taken together, our results demonstrate that an early loss of Ad's stimulatory effect on FA oxidation precedes an increase in plasmalemmal FA transporters and the accumulation of intramuscular DAG and ceramide, blunted insulin signaling, and ultimately impaired maximal insulin-stimulated glucose transport in skeletal muscle induced by HF diets.

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High-Fat Diet-Mediated Lipotoxicity and Insulin Resistance Is Related to Impaired Lipase Expression in Mouse Skeletal Muscle

Endocrinology ◽

10.1210/en.2012-2029 ◽

2013 ◽

Vol 154 (4) ◽

pp. 1444-1453 ◽

Cited By ~ 56

Author(s):

Pierre-Marie Badin ◽

Isabelle K. Vila ◽

Katie Louche ◽

Aline Mairal ◽

Marie-Adeline Marques ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Kinase ◽

Protein Content ◽

Insulin Signaling ◽

High Fat Diet ◽

Whole Body ◽

Wild Type ◽

High Fat ◽

Lipase Expression

Abstract Elevated expression/activity of adipose triglyceride lipase (ATGL) and/or reduced activity of hormone-sensitive lipase (HSL) in skeletal muscle are causally linked to insulin resistance in vitro. We investigated here the effect of high-fat feeding on skeletal muscle lipolytic proteins, lipotoxicity, and insulin signaling in vivo. Five-week-old C3H mice were fed normal chow diet (NCD) or 45% kcal high-fat diet (HFD) for 4 weeks. Wild-type and HSL knockout mice fed NCD were also studied. Whole-body and muscle insulin sensitivity, as well as lipolytic protein expression, lipid levels, and insulin signaling in skeletal muscle, were measured. HFD induced whole-body insulin resistance and glucose intolerance and reduced skeletal muscle glucose uptake compared with NCD. HFD increased skeletal muscle total diacylglycerol (DAG) content, protein kinase Cθ and protein kinase Cϵ membrane translocation, and impaired insulin signaling as reflected by a robust increase of basal Ser1101 insulin receptor substrate 1 phosphorylation (2.8-fold, P < .05) and a decrease of insulin-stimulated v-Akt murine thymoma viral oncogene homolog Ser473 (−37%, P < .05) and AS160 Thr642 (−47%, P <.01) phosphorylation. We next showed that HFD strongly reduced HSL phosphorylation at Ser660. HFD significantly up-regulated the muscle protein content of the ATGL coactivator comparative gene identification 58 and triacylglycerol hydrolase activity, despite a lower ATGL protein content. We further show a defective skeletal muscle insulin signaling and DAG accumulation in HSL knockout compared with wild-type mice. Together, these data suggest a pathophysiological link between altered skeletal muscle lipase expression and DAG-mediated insulin resistance in mice.

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Increased rate of whole body lipolysis before and after 9 days of bed rest in healthy young men born with low birth weight

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00223.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. E555-E564 ◽

Cited By ~ 26

Author(s):

A. C. Alibegovic ◽

L. Højbjerre ◽

M. P. Sonne ◽

G. van Hall ◽

T. J. Alsted ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Birth Weight ◽

Low Birth Weight ◽

Abdominal Obesity ◽

Bed Rest ◽

Hepatic Insulin Resistance ◽

Whole Body ◽

Peripheral Insulin Resistance ◽

Before And After

Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls. The basal rate of whole body lipolysis (WBL) was elevated in LBW subjects with and without correction for abdominal obesity before and after bed rest (all P = 0.01). Skeletal muscle hormone-sensitive lipase (HSL) protein expression and phosphorylation at Ser565 were similar in the two groups. Bed rest resulted in a decrease in WBL and an increased skeletal muscle HSL Ser565 phosphorylation indicating a decreased HSL activity in both groups. All subjects developed peripheral insulin resistance in response to bed rest (all P < 0.0001) with no differences between groups. LBW subjects developed hepatic insulin resistance in response to bed rest. In conclusion, increased WBL may contribute to the development of hepatic insulin resistance when exposed to bed rest in LBW subjects. Nine days of bed rest causes severe peripheral insulin resistance and reduced WBL and skeletal muscle HSL activity, as well as a compensatory increased insulin secretion, with no differences in LBW subjects and controls.

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