Expression and localization of GPR91 and GPR99 in murine organs

Diehl, J. M.; Gries, Barbara; Pfeil, Uwe; Goldenberg, Anna; Mermer, Petra; Kummer, Wolfgang; Paddenberg, Renate

doi:10.1007/s00441-015-2318-1

Cited by 41 publications

(31 citation statements)

References 41 publications

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“…However, there is no known role of OXGR1’s effects on fat thermogenesis and lipolysis. We found that while OXGR1 is widely expressed in many tissues, adrenal glands, testes, and brain have the highest expression of GRP99, which is consistent with a previous report (Diehl et al, 2016). Importantly, OXGR1 is highly expressed inside the adrenal gland medulla but not adrenal cortex, the main region that releases E. These results suggest a possible mediating role of OXGR1 in the stimulatory effects of AKG on E release.…”

Section: Discussionsupporting

confidence: 93%

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

Yuan

Jiang

et al. 2019

Preprint

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Running title: α-ketoglutaric acid stimulates lipolysis through OXGR1 31 32 Conflict of interest statement 33The authors have declared that no conflict of interest exists. 34 35 36 37 38 39 40 41 42 43 44 3 Summary: Beneficial effects of resistance exercise on metabolic health and particularly muscle 45hypertrophy and fat loss are well established, but the underlying chemical and physiological 46 mechanisms are not fully understood. Here we identified a myometabolite-mediated metabolic 47 pathway that is essential for the beneficial metabolic effects of resistance exercise in vivo. We showed 48 that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is 49 a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is 50 also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle 51 hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in 52 vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate 53 receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and 54 gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated 55 exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for 56 the salutary effects of resistance exercise, using AKG as a systemically-derived molecule for adrenal 57 stimulation of muscle hypertrophy and fat loss. 58 59 Keywords: AKG/lipolysis /obesity/OXGR1/thermogenesis. 60 61 62 63 64 5 provide signatures of endurance exercise performance and cardiovascular disease susceptibility, and 88also identify molecular pathways that may modulate the salutary effects on cardiovascular function. 89However, very few metabolomics data is available for resistance exercise (Berton et al, 2017; Li et al, 90 2012), and the underlying chemical and physiological mechanisms for the stimulatory effects of 91 resistance exercise on fat loss and muscle hypertrophy are not fully understood. Our goal is to identify 92 the essential mediator for the beneficial metabolic effects of resistance exercise and provide potential 93 therapeutic strategies to mimic the health effects of resistance exercise to combat obesity. 94 95Emerging evidence has identified skeletal muscle as secretory organs in regulating energy 96 homeostasis and obesity progression in other tissues (Ibrahim et al, 2017; Rai & Demontis, 2016). 97Exercise can induce systemic metabolic effects either via changes in the mass and metabolic demand 98 of muscle or via the release of muscle-derived cytokines (myokines) and metabolites (myometabolites) 99

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Section: Discussionsupporting

confidence: 93%

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

Yuan

Jiang

et al. 2019

Preprint

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“…GPR99 was considered a typical receptor for AKG22, whereas GPR91 responded to succinate2324. Given that AKG is a dicarboxylic acid similar to succinate, GPR91 and GPR99 could sense extracellular AKG concentration21.…”

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confidence: 99%

RETRACTED ARTICLE: Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways

Cai

Zhu

et al. 2016

Sci Rep

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Skeletal muscle weight loss is accompanied by small fiber size and low protein content. Alpha-ketoglutarate (AKG) participates in protein and nitrogen metabolism. The effect of AKG on skeletal muscle hypertrophy has not yet been tested, and its underlying mechanism is yet to be determined. In this study, we demonstrated that AKG (2%) increased the gastrocnemius muscle weight and fiber diameter in mice. Our in vitro study also confirmed that AKG dose increased protein synthesis in C2C12 myotubes, which could be effectively blocked by the antagonists of Akt and mTOR. The effects of AKG on skeletal muscle protein synthesis were independent of glutamate, its metabolite. We tested the expression of GPR91 and GPR99. The result demonstrated that C2C12 cells expressed GPR91, which could be upregulated by AKG. GPR91 knockdown abolished the effect of AKG on protein synthesis but failed to inhibit protein degradation. These findings demonstrated that AKG promoted skeletal muscle hypertrophy via Akt/mTOR signaling pathway. In addition, GPR91 might be partially attributed to AKG-induced skeletal muscle protein synthesis.

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“…As an important intermediate product in tricarboxylic acid cycles, AKG acts not only as the ligand for GPR99 receptor but also as a sensor of PHDs. Because only PHDs but not GPR99 express in the skeletal muscle (46), we wondered if PHDs act as downstream targets for AKG to mediate its antiprotein degradation effects. PHDs are a family of AKG-dependent dioxygenases, including PHD1-3 (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

et al. 2017

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Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. α-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3), one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the β adrenergic receptor (ADRB2) as a downstream target for PHD3. We found AKG inhibited PHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise-generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.-Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., Shu, G. α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway.

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Expression and localization of GPR91 and GPR99 in murine organs

Cited by 41 publications

References 41 publications

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

RETRACTED ARTICLE: Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways

α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

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