SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis

Zaganjor, Elma; Yoon, Haejin; Spinelli, Jessica B.; Nunn, Elizabeth R.; Laurent, Gaëlle; Keskinidis, Paulina; Sivaloganathan, Suganja; Joshi, Shakchhi; Notarangelo, Giulia; Mulei, Stacy; Chvasta, Mathew T.; Tucker, Sarah A.; Kalafut, Krystle; Ven, Robert A. H. van de; Clish, Clary B.; Haigis, Marcia C.

doi:10.1016/j.celrep.2021.109345

Cited by 39 publications

(40 citation statements)

References 29 publications

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“…During the remainder of oxidation BCAA carbons are either lost as CO 2 or contribute carbons to the tricarboxylic acid (TCA) cycle as succinyl-CoA or acetyl-CoA (Neinast et al, 2019a). In adipogenesis, a mitochondrial sirtuin, SIRT4, promotes leucine catabolism by increasing the activity of methylcrotonyl-CoA carboxylase (MCCC1), an enzyme that catalyzes the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA (Anderson et al, 2017;Zaganjor et al, 2021). The induction of leucine catabolism occurs early in the process of differentiation and further promotes PPARγ function (Zaganjor et al, 2021).…”

Section: Metabolic Regulation Of Adipogenesismentioning

confidence: 99%

“…In adipogenesis, a mitochondrial sirtuin, SIRT4, promotes leucine catabolism by increasing the activity of methylcrotonyl-CoA carboxylase (MCCC1), an enzyme that catalyzes the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA (Anderson et al, 2017;Zaganjor et al, 2021). The induction of leucine catabolism occurs early in the process of differentiation and further promotes PPARγ function (Zaganjor et al, 2021). Adipogenesis reduces the contribution of glutamine carbon to fatty acids and instead promotes de novo glutamine synthesis (Green et al, 2016).…”

Section: Metabolic Regulation Of Adipogenesismentioning

confidence: 99%

“…Compartment-specific alterations in NAD+ levels may also impact sirtuin activity. Increased mitochondrial NAD+ may promote the activity of SIRT4, an inducer of adipogenesis, while decreased nuclear NAD+ may decrease the activity of SIRT1, a negative regulator of adipogenesis (Mayoral et al, 2015;Zaganjor et al, 2021). NAD+ compartmentalization and availability may fine-tune adipogenesis via multiple independent mechanisms.…”

Section: Nad+mentioning

confidence: 99%

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Weighing in on Adipogenesis

2022

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Obesity is a growing health concern worldwide because of its contribution to metabolic syndrome, type II diabetes, insulin resistance (IR), and numerous cancers. In obesity, white adipose tissue (WAT) expands through two mechanisms: increase in adipocyte cell number by precursor cell differentiation through the process of adipogenesis (hyperplasia) and increase in existing mature adipocyte cell size (hypertrophy). While hypertrophy is associated with the negative effects of obesity on metabolic health, such as inflammation and lipotoxicity, adipogenesis prevents obesity-mediated metabolic decline. Moreover, in metabolically healthy obesity adipogenesis is increased. Thus, it is vital to understand the mechanistic basis for adipose expansion to inform novel therapeutic approaches to mitigate the dysfunction of this tissue and associated diseases. In this mini-review, we summarize recent studies on the regulation of adipogenesis and provide a perspective on targeting adipogenesis as a potential therapeutic avenue for metabolic disorders.

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Section: Metabolic Regulation Of Adipogenesismentioning

confidence: 99%

Section: Metabolic Regulation Of Adipogenesismentioning

confidence: 99%

Section: Nad+mentioning

confidence: 99%

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Weighing in on Adipogenesis

2022

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“…This pathway is upregulated during the initial stages of adipocyte differentiation (6)(7)(8)(9)(10)(11)(12) and is highly active in brown adipose tissue where BCAA catabolism is required to maintain thermogenesis in mice (5). Catabolism of BCAAs in adipocytes is initiated by mitochondrial BCAT2, which transfers the amino nitrogen to α-ketoglutarate yielding glutamate and a corresponding branched-chain α-keto acid (BCKA).…”

Section: Introductionmentioning

confidence: 99%

“…While diverse tissues use this pathway for energy generation, signaling, and biosynthesis ( 1, 2 ), adipose tissue is increasingly appreciated as an important contributor to BCAA homeostasis ( 3-7 ). This pathway is upregulated during the initial stages of adipocyte differentiation ( 6-12 ) and is highly active in brown adipose tissue where BCAA catabolism is required to maintain thermogenesis in mice ( 5 ). Catabolism of BCAAs in adipocytes is initiated by mitochondrial BCAT2, which transfers the amino nitrogen to α-ketoglutarate yielding glutamate and a corresponding branched-chain α-keto acid (BCKA).…”

Section: Introductionmentioning

confidence: 99%

Impaired BCAA catabolism during adipocyte differentiation decreases glycolytic flux

Green

Wessendorf-Rodriguez

Turner

et al. 2022

Preprint

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ObjectiveAdipocytes upregulate branched-chain amino acid (BCAA) catabolism during differentiation, but the downstream metabolic and biological impacts of this induction remain unclear. Here we sought to understand how BCAA catabolism supports intermediary metabolism and function in cultured adipocytes.MethodsUsing CRISPR/Cas9 gene-editing, we generated 3T3-L1 pre-adipocytes deficient in either branched-chain ketoacid dehydrogenase, subunit alpha (Bckdha) or acyl-CoA dehydrogenase 8 (Acad8), which predominantly metabolizes valine-derived isobutyryl-CoA, and examined their metabolism after differentiation. We performed stable-isotope tracing and mass spectrometry, developed a 13C metabolic flux analysis (13C-MFA) model incorporating central carbon metabolism and lipid biosynthesis, and performed RNA-sequencing to further explore functional changes.ResultsGeneration of polyclonal cultures deficient in Bckdha resulted in a 90%+ decrease in [U-13C6]leucine labeling in citrate in differentiated adipocytes (p<0.001). Lipid droplet accumulation and mRNA levels of key markers of adipocyte differentiation were unaffected by Bckdha deficiency; however, gene set enrichment analysis (GSEA) indicated adipogenesis and glycolysis were the primary downregulated pathways in these cells. Bckdha-deficient adipocytes had decreased glucose uptake (p<0.05), glycolytic flux (p<0.05), and increased glutamine contribution to the TCA cycle (p<0.05). These findings were supported by reduced lactate secretion (p<0.001) and oxygen consumption rates (p<0.05) and correlated with the transcriptional changes observed in adipocytes. Total de novo fatty acid synthesis flux was maintained but levels of odd-chain fatty acids and branched-chain fatty acids were reduced, as was the C16:1/C16:0 ratio. 13C-MFA confirmed these changes and highlighted the complex relationship between the TCA cycle, BCAA catabolism, and mitochondrial respiration. Finally, Acad8 deficiency resulted in far fewer differentially expressed genes compared to Bckdha deficiency and milder metabolic changes overall.ConclusionsThese findings highlight key metabolic and transcriptional changes that occur due to Bckdha deficiency in adipocytes and identify important links between BCAA catabolism, glycolytic flux, and respiration.HighlightsBckdha deficiency reduced glycolysis and lactate secretion in adipocytesPyruvate and glutamine contribution to TCA metabolism and acetyl-CoA increasedde novo fatty acid synthesis flux was maintained but fatty acid diversity decreasedRNA-seq data highlighted regulation of genes in glycolysis, adipogenesis, and EMTAcad8 deficiency resulted in fewer altered transcripts and milder metabolic changes

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SIRT4 in ageing

Qingcheng

Cheng

et al. 2023

Biogerontology

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SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis

Cited by 39 publications

References 29 publications

Weighing in on Adipogenesis

Weighing in on Adipogenesis

Impaired BCAA catabolism during adipocyte differentiation decreases glycolytic flux

SIRT4 in ageing

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