Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men

Bak, Ann Mosegaard; Vendelbo, Mikkel Holm; Christensen, Britt; Viggers, Rikke; Bibby, Bo Martin; Rungby, Jørgen; Jørgensen, Jens Otto Lunde; Møller, Niels; Jessen, Niels

doi:10.1371/journal.pone.0200817

Cited by 25 publications

(24 citation statements)

References 57 publications

(75 reference statements)

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“…The observed increases in “3‐hydroxybutyryl‐carnitine” and other acylcarnitines suggest that energy supply exceeds the resting energy requirements during prolonged fasting. Our findings are in accordance with data from metabolomics on skeletal muscle during prolonged fasting (Bak et al, ). In humans, the maximal capacity for β‐oxidation can be reached during intravenous lipid infusion in human subjects (Gormsen et al, ).…”

Section: Discussionsupporting

confidence: 93%

Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men

et al. 2019

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Fasting in human subjects shifts skeletal muscle metabolism toward lipid utilization and accumulation, including intramyocellular lipid (IMCL) deposition. Growth hormone (GH) secretion amplifies during fasting and promotes lipolysis and lipid oxidation, but it is unknown to which degree lipid deposition and metabolism in skeletal muscle during fasting depends on GH action. To test this, we studied nine obese but otherwise healthy men thrice: (a) in the postabsorptive state (“CTRL”), (b) during 72‐hr fasting (“FAST”), and (c) during 72‐hr fasting and treatment with a GH antagonist (GHA) (“FAST + GHA”). IMCL was assessed by magnetic resonance spectroscopy (MRS) and blood samples were drawn for plasma metabolomics assessment while muscle biopsies were obtained for measurements of regulators of substrate metabolism. Prolonged fasting was associated with elevated GH levels and a pronounced GHA‐independent increase in circulating medium‐ and long‐chain fatty acids, glycerol, and ketone bodies indicating increased supply of lipid intermediates to skeletal muscle. Additionally, fasting was associated with a release of short‐, medium‐, and long‐chain acylcarnitines to the circulation from an increased β‐oxidation. This was consistent with a ≈55%–60% decrease in pyruvate dehydrogenase (PDHa) activity. Opposite, IMCL content increased ≈75% with prolonged fasting without an effect of GHA. We suggest that prolonged fasting increases lipid uptake in skeletal muscle and saturates lipid oxidation, both favoring IMCL deposition. This occurs without a detectable effect of GHA on skeletal muscle lipid metabolism.

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Section: Discussionsupporting

confidence: 93%

Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men

et al. 2019

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“…Recently, a study focused on skeletal muscle was carried out in lean and obese men to explore and compare substrate metabolism in such tissue after fasting conditions (Table 2 ) (Bak et al 2018 ). Interestingly, β-hydroxybutyrate was found elevated in plasma, being more pronounced in lean than obese.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, α-hydroxybutyrate has been investigated as an early marker of both IR and impaired glucose regulation in a nondiabetic population (Gall et al 2010 ). Furthermore, the ketone body β-hydroxybutyrate was highly elevated in the skeletal muscle of obese men (more than in lean) during prolonged fasting (up to 72 h) (Bak et al 2018 ). The greater increment of ketone bodies in obesity status might be the result of the increased catabolism of more available BCAAs, but increased metabolization of intracellular skeletal fat mass could also contribute to the increased production of ketone bodies.…”

Section: Discussionmentioning

confidence: 99%

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Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies

2019

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Introduction Obesity is a disorder characterized by a disproportionate increase in body weight in relation to height, mainly due to the accumulation of fat, and is considered a pandemic of the present century by many international health institutions. It is associated with several non-communicable chronic diseases, namely, metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and cancer. Metabolomics is a useful tool to evaluate changes in metabolites due to being overweight and obesity at the body fluid and cellular levels and to ascertain metabolic changes in metabolically unhealthy overweight and obese individuals (MUHO) compared to metabolically healthy individuals (MHO). Objectives We aimed to conduct a systematic review (SR) of human studies focused on identifying metabolomic signatures in obese individuals and obesity-related metabolic alterations, such as inflammation or oxidative stress. Methods We reviewed the literature to identify studies investigating the metabolomics profile of human obesity and that were published up to May 7th, 2019 in SCOPUS and PubMed through an SR. The quality of reporting was evaluated using an adapted of QUADOMICS. Results Thirty-three articles were included and classified according to four types of approaches. (i) studying the metabolic signature of obesity, (ii) studying the differential responses of obese and non-obese subjects to dietary challenges (iii) studies that used metabolomics to predict weight loss and aimed to assess the effects of weight loss interventions on the metabolomics profiles of overweight or obese human subjects (iv) articles that studied the effects of specific dietary patterns or dietary compounds on obesity-related metabolic alterations in humans. Conclusion The present SR provides state-of-the-art information about the use of metabolomics as an approach to understanding the dynamics of metabolic processes involved in human obesity and emphasizes metabolic signatures related to obesity phenotypes.

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“…Boxes represent median and interquartile range with 95% confidence intervals as whiskers. See also Supplementary Table 6 related metabolites following prolonged fasting in humans (Bak et al 2018).…”

Section: Oral Glucose Tolerancementioning

confidence: 99%

Short-term time-restricted feeding is safe and feasible in non-obese healthy midlife and older adults

et al. 2020

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Chronic calorie restriction (CR) improves cardiovascular function and several other physiological markers of healthspan. However, CR is impractical in non-obese older humans due to potential loss of lean mass and bone density, poor adherence, and risk of malnutrition. Time-restricted feeding (TRF), which limits the daily feeding period without requiring a reduction in calorie intake, may be a promising alternative healthspan-extending strategy for midlife and older adults; however, there is limited evidence for its feasibility and efficacy in humans. We conducted a randomized, controlled pilot study to assess the safety, tolerability, and overall feasibility of short-term TRF (eating <8 h day −1 for 6 weeks) without weight loss in healthy non-obese midlife and older adults, while gaining initial insight into potential efficacy for improving cardiovascular function and other indicators of healthspan. TRF was safe and well-tolerated, associated with excellent adherence and reduced hunger, and did not influence lean mass, bone density, or nutrient intake. Cardiovascular function was not enhanced by short-term TRF in this healthy cohort, but functional (endurance) capacity and glucose tolerance were modestly improved. These results provide a foundation for conducting larger clinical studies of TRF in midlife and older adults, including trials with a longer treatment duration.

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Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men

Cited by 25 publications

References 57 publications

Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men

Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men

Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies

Short-term time-restricted feeding is safe and feasible in non-obese healthy midlife and older adults

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