bims-mimead 2024-11-24 papers

bims-mimead

Biomed News

on Mitochondrial metabolism in ageing and metabolic disease

Issue of 2024–11–24
seven papers selected by
Rachel M. Handy, University of Guelph

Crosstalk between pancreatic cancer and adipose tissue: Molecular mechanisms and therapeutic implications.
Integrating transcriptomics and proteomics to understand the molecular mechanisms underlying the pathogenesis of type 2 diabetes mellitus.
Revisiting the concepts of de novo lipogenesis to understand the conversion of carbohydrates into fats: Stop overvaluing and extrapolating the renowned phrase "fat burns in the flame of carbohydrate".
Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.
Exploring differential miRNA expression profiles in muscular and visceral adipose tissue of patients with severe obesity.
Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway.

Biochem Biophys Res Commun. 2024 Nov 15. pii: S0006-291X(24)01548-1. [Epub ahead of print]740 151012

Crosstalk between pancreatic cancer and adipose tissue: Molecular mechanisms and therapeutic implications.

Boyu Diao, Zhiyao Fan, Bin Zhou, Hanxiang Zhan.

  The incidence rate of pancreatic cancer, a fatal illness with a meager 5-year survival rate, has been on the rise in recent times. When individuals accumulate excessive amounts of adipose tissue, the adipose organ becomes dysfunctional due to alterations in the adipose tissue microenvironment associated with inflammation and metabolism. This phenomenon may potentially contribute to the aberrant accumulation of fat that initiates pancreatic carcinogenesis, thereby influencing the disease's progression, resistance to treatment, and metastasis. This review presents a summary of the impact of pancreatic steatosis, visceral fat, cancer-associated adipocytes and lipid diets on the advancement of pancreatic cancer, as well as the reciprocal effects of pancreatic cancer on adipose tissue. Understanding the molecular mechanisms underlying the relationship between dysfunctional adipose tissue and pancreatic cancer better may lead to the discovery of new therapeutic targets for the disease's prevention and individualized treatment. This is especially important given the rising global incidence of obesity, which will improve the pancreatic cancer treatment options that are currently insufficient.

Keywords:  Adipose tissue; Cancer-associated adipocytes; Metabolism; Pancreatic cancer; Visceral fat

DOI:  https://doi.org/10.1016/j.bbrc.2024.151012
Genomics. 2024 Nov 19. pii: S0888-7543(24)00185-X. [Epub ahead of print] 110964

Integrating transcriptomics and proteomics to understand the molecular mechanisms underlying the pathogenesis of type 2 diabetes mellitus.

Shuyao Wei, Feifei Ma, Shanshan Feng, Xiaoqin Ha.

  The liver plays an important role in glucose regulation, and their dysfunction is closely associated with the development of type 2 diabetes mellitus (T2DM), and insulin resistance (IR) in hepatocyte mediate the pathogenesis of diabetes mellitus. In T2DM rats and their correlated control, we investigated various genes expression at transcriptional and translational level by utilizing transcriptomic using RNA sequencing (RNA-seq) and proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to disclose potential candidates for Type 2 diabetes diagnosis and therapy. We found the lecithin retinol acyltransferase (Lrat) gene regulate hepatocyte IR in T2DM. Furthermore, BRL-3A cells, rat liver cells, worked as the IR model in vitro study. Hence, Lrat gene was overexpressed in BRL-3A cells to explore the role of Lrat gene in IR by measuring the cellular glucose consumption, TCHO, and LDL-C levels. Finally, we found that Lrat gene can improve the level of glycolipid metabolism in BRL-3A cells and reduce the degree of IR in BRL-3A cells. Therefore, further exploration of Lrat gene related molecular mechanism is meaningful.

Keywords:  Insulin resistance; Lecithin retinol acyltransferase; Proteomics; Transcriptomics; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.ygeno.2024.110964
Nutrition. 2024 Oct 24. pii: S0899-9007(24)00266-1. [Epub ahead of print]130 112617

Revisiting the concepts of de novo lipogenesis to understand the conversion of carbohydrates into fats: Stop overvaluing and extrapolating the renowned phrase "fat burns in the flame of carbohydrate".

Heitor O Santos, Nilson Penha-Silva.

  Carbohydrates can be converted into fatty acids via de novo lipogenesis (DNL). Although DNL is considered inefficient, these endogenous fatty acids contribute substantially to the esterification pathway in adipose tissue, together with fatty acids of feeding. This article revisited the concepts of DNL and aimed to discuss the clinical magnitude of carbohydrate overfeeding and fat mass accumulation. Although fat storage resulting from fat intake is more favorable for fat mass accrual than carbohydrates due to molecule structure and metabolism (e.g., oxidation and thermic effect), carbohydrates can substantially participate in lipogenesis and esterification under excess carbohydrate intake over time. Regarding only monosaccharide overfeeding, glucose and fructose favor the subcutaneous and visceral adipose tissue, respectively. While fructose and sucrose are considered villains in nonalcoholic fatty liver disease, energy surplus from carbohydrates, regardless of sources, can be considered an underlying cause of obesity. Interestingly, some degree of DNL in adipocytes may be favorable to mitigate a high deposition of fatty acids in the liver, conferring a physiological role. Although "fat burns in the flame of carbohydrate" is a praiseworthy phrase that has helped describe basic concepts in biochemistry for many decades, it appears to be overvalued and extrapolated even nowadays. DNL cannot be neglected. It is time to consider DNL an efficient biochemical process in health and disease.

Keywords:  Fat mass; Fructose; Glucose; High-carbohydrate diet; Obesity; de novo lipogenesis

DOI:  https://doi.org/10.1016/j.nut.2024.112617
Cell Metab. 2024 Nov 18. pii: S1550-4131(24)00416-9. [Epub ahead of print]

Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.

Elise J Needham, Janne R Hingst, Johan D Onslev, Alexis Diaz-Vegas, Magnus R Leandersson, Hannah Huckstep, Jonas M Kristensen, Kohei Kido, Erik A Richter, Kurt Højlund, Benjamin L Parker, Kristen Cooke, Guang Yang, Christian Pehmøller, Sean J Humphrey, David E James, Jørgen F P Wojtaszewski.

  Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by "priming" a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.

Keywords:  MINDY1; cell signaling; exercise; insulin; insulin resistance; phosphoproteomics; proteomics; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.10.020
Int J Obes (Lond). 2024 Nov 19.

Exploring differential miRNA expression profiles in muscular and visceral adipose tissue of patients with severe obesity.

Carmen Lambert, Paula Morales-Sánchez, Ana Victoria García, Elsa Villa-Fernández, Jèssica Latorre, Miguel García-Villarino, Estrella Olga Turienzo Santos, Lorena Suárez-Gutierrez, Raquel Rodríguez Uría, Sandra Sanz Navarro, Jessica Ares-Blanco, Pedro Pujante, Lourdes María Sanz Álvarez, Edelmiro Menéndez-Torre, María Moreno Gijón, José Manuel Fernandez-Real, Elías Delgado.

BACKGROUND: This study aims to investigate the differential miRNA expression profile between the visceral white adipose tissue and the skeletal muscle of people with obesity undergoing bariatric surgery.
METHODS: Skeletal muscle and visceral adipose tissue samples of 10 controls and 38 people with obesity (50% also with type 2 diabetes) undergoing bariatric surgery were collected. miRNA expression profiles were analyzed using Next-Generation Sequencing and subsequently validated using RT-PCR.
RESULTS: Approximately 69% of miRNAs showed similar expression in both tissues, however, 55 miRNAs were preferentially expressed in visceral adipose tissue and 53 in skeletal muscle. miR-122b-5p was uniquely identified in skeletal muscle, while miR-1-3p and miR-206 were upregulated in skeletal muscle. Conversely, miR-224-5p and miR-335-3p exhibited upregulation in visceral adipose tissue. Notably, distinctions related to the presence of type 2 diabetes were observed solely in the expression of miR-1-3p and miR-206 in visceral adipose tissue.
CONCLUSIONS: This is the first study unveiling distinct miRNA expression profiles in paired samples of visceral adipose tissue and skeletal muscle in humans. The identification of obesity-specific miRNAs in these tissues opens up promising avenues for research into potential biomarkers for obesity diagnosis and treatment.

DOI: https://doi.org/10.1038/s41366-024-01683-4
J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004

Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.

Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.

  Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.

Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux

DOI:  https://doi.org/10.1016/j.jbc.2024.108004
Acta Pharmacol Sin. 2024 Nov 20.

Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway.

Ji Wang, Meng-Yu Zhong, Yun-Xia Liu, Jia-Yu Yu, Yi-Bin Wang, Xue-Jiao Zhang, Hai-Peng Sun.

  Branched-chain amino acids (BCAAs) including leucine, isoleucine and valine have been linked with metabolic and cardiovascular diseases. BCAAs homeostasis is tightly controlled by their catabolic pathway. BCKA dehydrogenase (BCKD) complex is the rate-limiting step for BCAA catabolism. Mitochondrial phosphatase 2C (PP2Cm) dephosphorylates the BCKD E1alpha subunit and activates BCKD complex. Deficiency of PP2Cm impairs BCAA catabolism, leading to higher plasma BCAA concentrations. Emerging evidence shows that bile acids are key regulators of glucose, lipid and energy metabolism. In this study, we investigated whether a direct link existed between BCAAs and bile acids metabolism. Wild-type mice were fed with normal-BCAA or high-BCAA diet, while PP2Cm deficiency mice were fed with normal chow for 14 weeks. The mice were fasted for 6 h before tissue harvest to exclude metabolic changes due to immediate food intake. We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow. These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, and 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of CYP7A1 in plasma. BCAAs induced Cyp7a1 expression in cultured hepatocytes. In mouse liver and cultured hepatocytes, we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21 (FGF21) expression and ERK signaling pathway. Direct inhibition of ERK by U0126 (800 nM) markedly induced Cyp7a1 expression in cultured hepatocytes. Moreover, the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes. Collectively, this study demonstrates a direct link between BCAAs and bile acid synthesis. BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway. BCAAs-regulated bile acid synthesis and homeostasis may contribute to developing novel therapeutic strategies for the treatment of metabolic disorders.

Keywords:  BCAAs; CYP7A1; ERK; FGF21; bile acid; metabolic disorders

DOI:  https://doi.org/10.1038/s41401-024-01417-2