bims-mimead 2024-12-29 papers

Issue of 2024–12–29
five papers selected by
Rachel M. Handy, University of Guelph

Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords: NAD; aging; metabolic rate; mice

DOI: https://doi.org/10.1111/acel.14462

FASEB J. 2024 Dec 13. 38(24): e70273

Targeting GSK-3β for adipose dysfunction and cardiovascular complications of metabolic disease: An entangled WNT/β-catenin question.

Nasser Alotaiq, Ahmed S Khalifa, Amr Youssef, Esraa G El-Nagar, Nasr Eldin Elwali, Hosam M Habib, Ibrahim AlZaim, Ali H Eid, Nour-Mounira Z Bakkar, Ahmed F El-Yazbi.

Individuals with metabolic syndrome have a high risk of developing cardiovascular disorders that is closely tied to visceral adipose tissue dysfunction, as well as an altered interaction between adipose tissue and the cardiovascular system. In metabolic syndrome, adipose tissue dysfunction is associated with increased hypertrophy, reduced vascularization, and hypoxia of adipocytes, leading to a pro-oxidative and pro-inflammatory environment. Among the pathways regulating adipose tissue homeostasis is the wingless-type mammary tumor virus integration site family (Wnt) signaling pathway, with both its canonical and non-canonical arms. Various modulators of the Wnt signaling have been identified to contribute to the development of metabolic diseases and their cardiovascular complications, with a particularly significant role played by Glycogen Synthase Kinase-3β (GSK-3β). GSK-3β levels and activities have various and often contrasting roles in obesity and related metabolic disorders, as well as their cardiovascular sequelae. Here, we explore the possibility that altered Wnt signaling and GSK-3β activities could serve as a connection between adipose tissue dysfunction and the development of cardiovascular disease in individuals with metabolic syndrome. We attempt to define a context-specific approach for intervention, which could possibly serve as a novel disease modifying therapy for the mitigation of such complications.

Keywords: Wnt/β‐catenin signaling; adipogenesis; adipose tissue; glycogen synthase kinase‐3β; hyperplasia; hypertrophy

DOI: https://doi.org/10.1096/fj.202402470R

Mol Nutr Food Res. 2024 Dec 20. e202400721

EPA/DHA but Not ALA Reduces Visceral Adiposity and Adipocyte Size in High Fat Diet-Induced Obese Delta-6 Desaturase Knockout Mice.

James N Smorenburg, Katarzyna Hodun, Patrick V McTavish, Chenxuan Wang, Marina A Pinheiro, Kyle R D Wells, Keith R Brunt, Manubu T Nakamura, Adrian Chabowski, David M Mutch.

The objective of this omega-3 feeding study was to elucidate the independent effects of α-linolenic acid (ALA) versus eicosapentaenoic (EPA)/docosahexaenoic acid (DHA) on visceral adiposity and inflammatory signaling in diet-induced obese delta-6 desaturase (Fads2) knockout (KO) mice. Male wildtype (WT) and Fads2 KO mice were fed a high-fat diet (45% kcal from fat) containing either lard (no omega-3s), flaxseed (ALA), or menhaden (EPA/DHA) for 21 weeks. Epididymal white adipose tissue (eWAT) was analyzed for changes in tissue weight, adipocyte size, triacylglycerol (TAG) and fatty acid content, and inflammatory markers. Despite no differences in final body weight, menhaden-fed mice had lower eWAT weight, smaller adipocytes, and lower TAG content compared to lard-fed mice regardless of Fads2 genotype. The eWAT of flaxseed-fed WT mice resembled menhaden-fed mice, while the eWAT of flaxseed-fed KO mice resembled lard-fed mice. No differences were observed in the expression of genes regulating eWAT inflammatory signaling (Tnfα, Nfκb, Mapk14, Mcp1, Ccl5, Tlr4, Nlrp3, or Adipoq) or the abundance of select proteins (p38-MAPK or MCP-1). In conclusion, a high-fat diet containing EPA/DHA, but not ALA, attenuates adipocyte hypertrophy and lowers TAG content but has no effect on eWAT inflammation in a mouse model of long-term diet-induced obesity.

Keywords: Fads2; epididymal adipose tissue; inflammation; omega‐3 long‐chain polyunsaturated fatty acids

DOI: https://doi.org/10.1002/mnfr.202400721

Lancet Reg Health Eur. 2024 Dec;47 101098

Why are we still in need for novel anti-obesity medications?

Aaron Novikoff, Gerald Grandl, Xue Liu, Timo D Müller.

From the pioneering moment in 1987 when the insulinotropic effect of glucagon-like peptide 1 (GLP-1) was first demonstrated in humans, to today's pharmaceutical gold rush for GLP-1-based treatments of obesity, the journey of GLP-1 pharmacology has been nothing short of extraordinary. The sequential conceptual developments of long-acting GLP-1 receptor (GLP-1R) mono-agonists, GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonists, and GLP-1R/GIPR/glucagon receptor (GcgR) triple agonists, have led to profound body weight-lowering capacities, with benefits that extend past obesity and towards obesity-associated diseases. The GLP-1R/GIPR dual-agonist tirzepatide has demonstrated a remarkable 23% body weight reduction in individuals with obesity over 72 weeks, eclipsing the average result achieved by certain types of bariatric surgery. Meanwhile, the GLP-1R/GIPR/GcgR triple-agonist retatrutide achieves similar body weight loss (∼25%) in just two-thirds of the time, potentially surpassing the efficacy of Roux-en-Y gastric bypass. These remarkable achievements rightfully raise the question whether and why there is still need for novel anti-obesity medications (AOMs) in the future.

Keywords: Anti-obesity medication (AOM); Diabetes; GIP; GLP-1; Obesity

DOI: https://doi.org/10.1016/j.lanepe.2024.101098

Mol Med. 2024 Dec 20. 30(1): 255

Increased expression levels of PIEZO1 in visceral adipose tissue in obesity and type 2 diabetes are triggered by mechanical forces and are associated with inflammation.

Victoria Catalán, Javier Gómez-Ambrosi, Beatriz Ramírez, Xabier Unamuno, Sara Becerril, Amaia Rodríguez, Jorge Baixauli, Gabriel Reina, Ana Sancho, Camilo Silva, Javier A Cienfuegos, Gema Frühbeck.

BACKGROUND: PIEZO1 has emerged as a mechanoreceptor linked with adipogenesis, adipose tissue (AT) inflammation and insulin resistance. We aimed to determine the impact of obesity and obesity-associated type 2 diabetes (T2D) as well as mechanical compression forces on the expression of PIEZO1 in visceral AT (VAT) and its relation with inflammation.
METHODS: Blood and VAT samples were obtained from 100 volunteers. Static compression studies in VAT explants were performed to study the PIEZO1 response. The effect of bariatric surgery on the expression of Piezo1 was assessed in a rat model of diet-induced obesity.
RESULTS: Obesity and obesity-associated T2D increased (P < 0.01) gene expression levels of PIEZO1 in VAT mainly due to adipocytes. SWELL1 and key markers of inflammation (NLRP3, NLRP6, IL1B, IL18 and IL8) were also upregulated in VAT in obesity and T2D being significantly associated (P < 0.01) with PIEZO1 levels. We further showed that the static compression of VAT explants promoted an upregulation of PIEZO1 (P < 0.01) and SWELL1 (P < 0.01) expression levels together with a strong increase in the expression and release of key inflammatory mediators. The treatment of THP-1-derived macrophages with the secretome of adipocytes from patients with obesity upregulated (P < 0.001) PIEZO1 levels. Rats undergoing bariatric surgery exhibited decreased (P < 0.01) expression levels of Piezo1 in the epididymal AT.
CONCLUSIONS: Static compression triggered an upregulation of PIEZO1 in VAT explants together with a strong inflammation. In addition, the increased expression of PIEZO1 in VAT in obesity and obesity-associated T2D, primarily attributable to adipocytes, is closely associated with SWELL1 and inflammatory markers.

Keywords: Inflammation; Mechanotransduction; Obesity; PIEZO1; Type 2 diabetes; VAT

DOI: https://doi.org/10.1186/s10020-024-01008-1