SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

Villanueva-Carmona, Teresa; Cedó, Lídia; Madeira, Ana; Ceperuelo-Mallafré, Victòria; Rodríguez-Peña, M-Mar; Núñez‐Roa, Catalina; Masip, Elsa Maymó-; Repollés-de-Dalmau, Maria; Badia, Joan R.; Keiran, Noelia; Mirasierra, Mercedes; Pimenta-Lopes, Carolina; Sabadell‐Basallote, Joan; Bosch, Ramón; Caubet, Laura; Gil, Joan Carles Escolà-; Fernández‐Real, José‐Manuel; Vilarrasa, Núria; Ventura, Francesc; Vallejo, Mario; Vendrell, Joan; Fernández‐Veledo, Sonia

doi:10.1016/j.cmet.2023.03.004

Cited by 21 publications

(7 citation statements)

References 109 publications

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“…SUCNR1 activation initiates interaction with heterotrimeric GTPases, thereby stimulating downstream signalling events that vary with cell type, leading to different downstream signals and effects in a cell-dependent manner. Succinate–SUCNR1 signalling has been implicated in various transduction pathways, such as ERK pathways in cardiomyocytes [ 24 ] and AMP-activated protein kinase (AMPK) pathways in adipocytes [ 25 ]. Though the desensitisation and internalisation processes of SUCNR1 are similar to those of other GPCRs, our understanding of these mechanisms remains rudimentary.…”

Section: Succinate: a Dual Metabolite From Multifaceted Perspectives—...mentioning

confidence: 99%

“…Studies have observed transiently elevated succinate levels during physiological states, like exercise [ 29 ] and food intake [ 30 ], implying additional metabolic functions. In this context, it has been revealed that SUCNR1 signalling contributes to paracrine communication in skeletal muscle during exercise, resulting in muscle remodelling [ 29 ] and controls leptin production by adipose tissue in response to food ingestion [ 25 ]. The transient increase in succinate levels, which appears to be essential for regulating physiological responses to exercise and feeding via SUCNR1, differs notably from the consequences of chronic succinate elevation that are observed in metabolic disorders.…”

Section: Succinate: a Dual Metabolite From Multifaceted Perspectives—...mentioning

confidence: 99%

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Type 2 diabetes and succinate: unmasking an age-old molecule

Fernández-Veledo,

Marsal-Beltran,

Vendrell

2024

Diabetologia

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Beyond their conventional roles in intracellular energy production, some traditional metabolites also function as extracellular messengers that activate cell-surface G-protein-coupled receptors (GPCRs) akin to hormones and neurotransmitters. These signalling metabolites, often derived from nutrients, the gut microbiota or the host’s intermediary metabolism, are now acknowledged as key regulators of various metabolic and immune responses. This review delves into the multi-dimensional aspects of succinate, a dual metabolite with roots in both the mitochondria and microbiome. It also connects the dots between succinate’s role in the Krebs cycle, mitochondrial respiration, and its double-edge function as a signalling transmitter within and outside the cell. We aim to provide an overview of the role of the succinate–succinate receptor 1 (SUCNR1) axis in diabetes, discussing the potential use of succinate as a biomarker and the novel prospect of targeting SUCNR1 to manage complications associated with diabetes. We further propose strategies to manipulate the succinate–SUCNR1 axis for better diabetes management; this includes pharmacological modulation of SUCNR1 and innovative approaches to manage succinate concentrations, such as succinate administration and indirect strategies, like microbiota modulation. The dual nature of succinate, both in terms of origins and roles, offers a rich landscape for understanding the intricate connections within metabolic diseases, like diabetes, and indicates promising pathways for developing new therapeutic strategies. Graphical Abstract

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Section: Succinate: a Dual Metabolite From Multifaceted Perspectives—...mentioning

confidence: 99%

Section: Succinate: a Dual Metabolite From Multifaceted Perspectives—...mentioning

confidence: 99%

Type 2 diabetes and succinate: unmasking an age-old molecule

Fernández-Veledo,

Marsal-Beltran,

Vendrell

2024

Diabetologia

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“…By influencing enzymatic activities, gene expression, and signaling pathways, signal metabolites orchestrate a wide array of physiological responses, spanning from adaptation to stress to the coordination of growth and differentiation [ 5 ]. Succinate, a key metabolite in the tricarboxylic acid cycle, has recently garnered significant attention for its intriguing role in the modulation of WAT physiology [ 60 , 94 ]. Emerging research has unveiled a novel connection between succinate and the conversion of white adipocytes to beige adipocytes, a process known as white-to-beige adipocyte conversion.…”

Section: Mitochondrial Role In Determining White Adipocyte Identitymentioning

confidence: 99%

The Emerging Importance of Mitochondria in White Adipocytes: Neither Last nor Least

Cai,

Wang,

Shao

2023

Endocrinol Metab

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The growing recognition of mitochondria’s crucial role in the regulation of white adipose tissue remodeling and energy balance underscores its significance. The marked metabolic diversity of mitochondria provides the molecular and cellular foundation for enabling adipose tissue plasticity in response to various metabolic cues. Effective control of mitochondrial function at the cellular level, not only in thermogenic brown and beige adipocytes but also in energy-storing white adipocytes, exerts a profound influence on adipose homeostasis. Furthermore, mitochondria play a pivotal role in intercellular communication within adipose tissue via production of metabolites with signaling properties. A more comprehensive understanding of mitochondrial regulation within white adipocytes will empower the development of targeted and efficacious strategies to enhance adipose function, leading to advancements in overall metabolic health.

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“…Extracellular succinate is a pleiotropic hormone-like metabolite that acts via its receptor, succinate receptor 1 (SUCNR1) (Fernandez-Veledo et al, 2021; He et al, 2004), that is widely expressed in human tissues (Gilissen et al, 2016) including epithelia of the intestine and kidney (Schneider et al, 2018), white adipose tissue and immunological tissue (Rubic et al, 2008). The close relationship between SUCNR1 and many inflammatory and metabolic diseases such as liver fibrosis (Winther et al, 2021), type 2 diabetes (Villanueva-Carmona et al, 2023), rheumatoid arthritis (Littlewood-Evans et al, 2016), dermatitis (Gnana-Prakasam et al, 2011), cancer metastasis (Wu et al, 2020), obesity (Keiran et al, 2019), and hypertension (Sadagopan et al, 2007), make this receptor an attractive target for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Structural insights into agonist binding and activation of succinate receptor 1

Liu,

Zhang

et al. 2024

Preprint

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Succinate is an intermediate of the citric acid cycle and serves important functions in energy homeostasis and metabolic regulation. Extracellular accumulation of succinate acts as a stress-induced signal through its G protein-coupled receptor, SUCNR1. Research on succinate signaling is hampered by the lack of high-resolution structures of the agonist-bound receptor. Here we present cryo-EM structures of SUCNR1-Gi complexes with the receptor bound to succinate and its non-metabolite derivative epoxysuccinate. Structural analysis of SUCNR1 identified key determinants for recognition of the dicarboxylate agonists in cis conformation. R2817.39 and Y832.64 are critical to ligand binding, but Y301.39 and R993.29 also participate in binding of succinate and epoxysuccinate, respectively. The extracellular loop 2, through F175ECL2 in its β-hairpin, forms a hydrogen bond with one of the carboxyl groups and serves as a lid to cap the binding pocket for succinate. At the receptor-Gi protein interface, agonist binding induces the rearrangement of a hydrophobic network on TM5 and TM6, leading to transmembrane signaling through TM3 and TM7. The agonist-bound SUCNR1 structures shed light on molecular recognition of succinate for receptor signaling, that may promote further development of novel agonists, antagonists and biased agonists targeting SUCNR1.

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SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

Cited by 21 publications

References 109 publications

Type 2 diabetes and succinate: unmasking an age-old molecule

Type 2 diabetes and succinate: unmasking an age-old molecule

The Emerging Importance of Mitochondria in White Adipocytes: Neither Last nor Least

Structural insights into agonist binding and activation of succinate receptor 1

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