PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle

Yoon, Haejin; Spinelli, Jessica B.; Zaganjor, Elma; Wong, Samantha J.; German, Natalie J.; Randall, Elizabeth C.; Dean, Afsah; Clermont, Allen C.; Paulo, João A.; Garcia, Daniel; Li, Hao; Rombold, Olivia; Agar, Nathalie Y.R.; Goodyear, Laurie J.; Shaw, Reuben J.; Gygi, Steven P.; Auwerx, Johan; Haigis, Marcia C.

doi:10.1016/j.cmet.2020.06.017

Cited by 26 publications

(13 citation statements)

References 66 publications

(78 reference statements)

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“…We found that D-allulose administration enhanced the AMPK axis, which is consistent with D-allulose enhancing the oxidation of fatty acids [24,25]. A strong fat-oxidation ability increases the endurance exercise capacity [22]. An increase in fat oxidation following D-allulose administration has been demonstrated in rats [24] and humans [25], which can explain the improved exercise performance observed in the present study.…”

Section: Discussionsupporting

confidence: 88%

“…Glycogen in muscles and the liver provides an energy source for aerobic performance [19], and glycogen accumulation can suppress body fatigue during exercise [20]. Alternatively, the efficient use of fat can contribute to exercise performance [21,22] and thus enhance endurance. We hypothesized that D-allulose would enhance exercise performance because its administration has been shown to increase muscle or liver glycogen storage and fat oxidation.…”

Section: Introductionmentioning

confidence: 99%

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d-Allulose Improves Endurance and Recovery from Exhaustion in Male C57BL/6J Mice

et al. 2022

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d-Allulose, a rare sugar, improves glucose metabolism and has been proposed as a candidate calorie restriction mimetic. This study aimed to investigate the effects of d-allulose on aerobic performance and recovery from exhaustion and compared them with the effects of exercise training. Male C57BL/6J mice were subjected to exercise and allowed to run freely on a wheel. Aerobic performance was evaluated using a treadmill. Glucose metabolism was analyzed by an intraperitoneal glucose tolerance test (ipGTT). Skeletal muscle intracellular signaling was analyzed by Western blotting. Four weeks of daily oral administration of 3% d-allulose increased running distance and shortened recovery time as assessed by an endurance test. d-Allulose administration also increased the maximal aerobic speed (MAS), which was observed following treatment for >3 or 7 days. The improved performance was associated with lower blood lactate levels and increased liver glycogen levels. Although d-allulose did not change the overall glucose levels as determined by ipGTT, it decreased plasma insulin levels, indicating enhanced insulin sensitivity. Finally, d-allulose enhanced the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase and the expression of peroxisome proliferator-activated receptor γ coactivator 1α. Our results indicate that d-allulose administration enhances endurance ability, reduces fatigue, and improves insulin sensitivity similarly to exercise training. d-Allulose administration may be a potential treatment option to alleviate obesity and enhance aerobic exercise performance.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

d-Allulose Improves Endurance and Recovery from Exhaustion in Male C57BL/6J Mice

et al. 2022

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“…We hypothesized that βPHD3KO islets might switch to an alternative energy source to sustain their function, namely, β-oxidation of fatty acids, which are present in excess during HFD feeding. Moreover, in cancer cells, PHD3 has been shown to increase activity of ACC2, which converts acetyl-CoA → malonyl-CoA, the latter suppressing carnitine palmitoyltransferase I (CPT1), the rate-limiting step in fatty acid oxidation ( 24 , 44 ). Indicating a profound change in β cell nutrient preference, supplementation of the culture medium with the fatty acid palmitate for 48–72 hours augmented glucose-stimulated and Extendin-4–potentiated insulin secretion in βPHD3KO islets after 4 weeks HFD ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

“…In both cases, identifying the PHD3 hydroxylation sites involved will be critical. However, assigning hydroxylation targets using mass spectrometry is currently controversial: misalignment of hydroxylation is frequently associated with the presence of residues in the tryptic fragment that can be artifactually oxidized ( 44 , 50 ). Thus, studies using animals lacking PHD3 and ACC1/ACC2 in β cells, or alternatively the use of (relatively) specific inhibitors, would be required to definitively link the carboxylase with the phenotype here.…”

Section: Discussionmentioning

confidence: 99%

Prolyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice

Nasteska¹,

Cuozzo²,

Viloria³

et al. 2021

JCI Insight

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The alpha ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is a Hypoxia-Inducible Factor (HIF) target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. While PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about effects of this highly conserved enzyme in insulin-secreting β-cells in vivo. Here, we show that deletion of PHD3 specifically in β-cells (βPHD3KO) is associated with impaired glucose homeostasis in mice fed high fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewire, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in βPHD3KO islets is associated with impaired glucose-stimulated ATP/ADP rises, Ca 2+ fluxes and insulin secretion. Thus, PHD3 might be a pivotal component of the β-cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress.

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“…Although the focus was on NAFLD and liver function (27), the authors did not report effects on skeletal muscle, that could potentially explain enhanced thermogenesis. For example, a recent study showed that global or skeletal muscle deletion of PHD3 led to enhanced exercise endurance capacity and a small increase in maximum oxygen consumption rate (VO2) due to increased fatty acid oxidation in muscle (30). We cannot directly compare the work by Laitakari et al to our study as they were conducted under different environmental temperatures (RT vs TN), disease (NAFLD vs basal) and genetic models (whole body vs adipose-specific targeting).…”

Section: Loss Of Phd2 In Adipocytes Increases Brown Adipocyte Prolifementioning

confidence: 88%

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Gómez

Cervera

Wang

et al. 2021

Preprint

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Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higher Ucp1 mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction of UCP1 mRNA expression by FG2216, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study revealed that serum PHD2 (aka EGLN1) associates with increased risk of metabolic disease. Our data suggest adipose–selective PHD2 inhibition as a novel therapeutic strategy for metabolic disease and identify serum PHD2 as a potential biomarker.

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PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle

Cited by 26 publications

References 66 publications

d-Allulose Improves Endurance and Recovery from Exhaustion in Male C57BL/6J Mice

d-Allulose Improves Endurance and Recovery from Exhaustion in Male C57BL/6J Mice

Prolyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

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