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

Siôn A Parry, Mark C Turner, Rachel M Woods, Lewis J James, Richard A Ferguson, Matthew Cocks, Katie L Whytock, Juliette A Strauss, Sam O Shepherd, Anton J M Wagenmakers, Gerrit van Hall, Carl J Hulston

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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.

Original languageEnglish
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Volume105
Issue number1
Early online date12 Sep 2019
DOIs
Publication statusPublished - 1 Jan 2020
Externally publishedYes

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Phosphorylation
Nitric Oxide Synthase Type III
Metabolism
Muscle
Fats
Insulin
Glucose
Muscles
Nutrition
Skeletal Muscle
Eating
Dietary Fats
Carbohydrates
Arterioles
Diet
Microvessels
Insulin Resistance
Chemical activation
Fluxes
Proteins

Bibliographical note

© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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High-Fat Overfeeding Impairs Peripheral Glucose Metabolism and Muscle Microvascular eNOS Ser1177 Phosphorylation. / Parry, Siôn A; Turner, Mark C; Woods, Rachel M; James, Lewis J; Ferguson, Richard A; Cocks, Matthew; Whytock, Katie L; Strauss, Juliette A; Shepherd, Sam O; Wagenmakers, Anton J M; van Hall, Gerrit; Hulston, Carl J.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 105, No. 1, 01.01.2020.

Research output: Contribution to journalArticle

Parry, SA, Turner, MC, Woods, RM, James, LJ, Ferguson, RA, Cocks, M, Whytock, KL, Strauss, JA, Shepherd, SO, Wagenmakers, AJM, van Hall, G & Hulston, CJ 2020, 'High-Fat Overfeeding Impairs Peripheral Glucose Metabolism and Muscle Microvascular eNOS Ser1177 Phosphorylation' Journal of Clinical Endocrinology and Metabolism, vol. 105, no. 1. https://doi.org/10.1210/clinem/dgz018
Parry, Siôn A ; Turner, Mark C ; Woods, Rachel M ; James, Lewis J ; Ferguson, Richard A ; Cocks, Matthew ; Whytock, Katie L ; Strauss, Juliette A ; Shepherd, Sam O ; Wagenmakers, Anton J M ; van Hall, Gerrit ; Hulston, Carl J. / High-Fat Overfeeding Impairs Peripheral Glucose Metabolism and Muscle Microvascular eNOS Ser1177 Phosphorylation. In: Journal of Clinical Endocrinology and Metabolism. 2020 ; Vol. 105, No. 1.
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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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AU - Parry, Siôn A

AU - Turner, Mark C

AU - Woods, Rachel M

AU - James, Lewis J

AU - Ferguson, Richard A

AU - Cocks, Matthew

AU - Whytock, Katie L

AU - Strauss, Juliette A

AU - Shepherd, Sam O

AU - Wagenmakers, Anton J M

AU - van Hall, Gerrit

AU - Hulston, Carl J

N1 - © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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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DO - 10.1210/clinem/dgz018

M3 - Article

VL - 105

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 1

ER -