bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–11–10
eleven papers selected by
Xiong Weng, University of Edinburgh
  1. CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
  2. Leptin in humans: Evidence from clinical studies and current and future clinical applications.
  3. Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.
  4. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.
  5. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  6. Metabolite signatures of chronological age, aging, survival, and longevity.
  7. Intricacies and obscurities of non-shivering thermogenesis.
  8. A multiorgan map of metabolic, signaling, and inflammatory pathways that coordinately control fasting glycemia in mice.
  9. Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems.
  10. Role of glycogen in cardiac metabolic stress.
  11. Quorum sensing orchestrates parallel cell death pathways in Vibrio cholerae via Type 6 secretion-dependent and -independent mechanisms.
  1. Nat Commun. 2024 Nov 02. 15(1): 9475
    CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
    Chuanhai Zhang, Mengchen Ye, Kamran Melikov, Dengbao Yang, Goncalo Dias do Vale, Jeffrey McDonald, Kaitlyn Eckert, Mei-Jung Lin, Xing Zeng.
      Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload in mice of both sexes.
    DOI:  https://doi.org/10.1038/s41467-024-53750-z
  2. Metabolism. 2024 Oct 26. pii: S0026-0495(24)00281-6. [Epub ahead of print] 156053
    Leptin in humans: Evidence from clinical studies and current and future clinical applications.
    Nikolaos Perakakis, Christos S Mantzoros.
      Leptin has been established as the prototype adipose tissue secreted hormone and as a major regulator of several human physiology functions. Here, we are primarily reviewing the findings from studies in humans involving leptin administration. We are describing the metabolic, endocrine and immunologic effects of leptin replacement in conditions of leptin deficiency, such as short-term fasting in healthy individuals, relative energy deficiency in sports (REDS), congenital leptin deficiency (CLD), generalized (GL) and partial lipodystrophy (PL), HIV-associated lipodystrophy (HIV-L) and of leptin treatment in conditions of leptin excess (common obesity, type 2 diabetes, steatotic liver disease). We are comparing the results with the findings from preclinical models and present the main conclusions regarding the role of leptin in human physiology, pathophysiology and therapeutics. We conclude that, in conditions of energy deficiency, leptin substitution effectively reduces body weight and fat mass through reduction of appetite, it improves hypertriglyceridemia, insulin resistance and hepatic steatosis (especially in GL and PL), it restores neuroendocrine function (especially the gonadotropic axis), it regulates adaptive immune system cell populations and it improves bone health. On the contrary, leptin treatment in conditions of leptin excess, such as common obesity and type 2 diabetes, does not improve any metabolic abnormalities. Strategies to overcome leptin tolerance/resistance in obesity and type 2 diabetes have provided promising results in animal studies, which should though be tested in humans in randomized clinical trials.
    Keywords:  Appetite; Diabetes; Energy; Expenditure; MASLD; Obesity
    DOI:  https://doi.org/10.1016/j.metabol.2024.156053
  3. Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00400-5. [Epub ahead of print]
    Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.
    Victor Gray, Weixin Chen, Rachael Julia Yuenyinn Tan, Jia Ming Nickolas Teo, Zhihao Huang, Carol Ho-Yi Fong, Tommy Wing Hang Law, Zi-Wei Ye, Shuofeng Yuan, Xiucong Bao, Ivan Fan-Ngai Hung, Kathryn Choon-Beng Tan, Chi-Ho Lee, Guang Sheng Ling.
      Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+ T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+ T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.
    Keywords:  T helper 1 responses; hyperglycemia; lipid peroxidation; protein carbonylation; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.004
  4. Nat Commun. 2024 Nov 04. 15(1): 9522
    PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.
    Eduardo H Gilglioni, Ao Li, Wadsen St-Pierre-Wijckmans, Tzu-Keng Shen, Israel Pérez-Chávez, Garnik Hovhannisyan, Michela Lisjak, Javier Negueruela, Valerie Vandenbempt, Julia Bauzá-Martinez, Jose M Herranz, Daria Ezeriņa, Stéphane Demine, Zheng Feng, Thibaut Vignane, Lukas Otero Sanchez, Flavia Lambertucci, Alena Prašnická, Jacques Devière, David C Hay, Jose A Encinar, Sumeet Pal Singh, Joris Messens, Milos R Filipovic, Hayley J Sharpe, Eric Trépo, Wei Wu, Esteban N Gurzov.
      Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.
    DOI:  https://doi.org/10.1038/s41467-024-53733-0
  5. Nature. 2024 Nov 06.
    Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
    Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.
      Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.
    DOI:  https://doi.org/10.1038/s41586-024-08146-w
  6. Cell Rep. 2024 Nov 05. pii: S2211-1247(24)01264-6. [Epub ahead of print]43(11): 114913
    Metabolite signatures of chronological age, aging, survival, and longevity.
    Paola Sebastiani, Stefano Monti, Michael S Lustgarten, Zeyuan Song, Dylan Ellis, Qu Tian, Michaela Schwaiger-Haber, Ethan Stancliffe, Anastasia Leshchyk, Meghan I Short, Andres V Ardisson Korat, Anastasia Gurinovich, Tanya Karagiannis, Mengze Li, Hannah J Lords, Qingyan Xiang, Megan M Marron, Harold Bae, Mary F Feitosa, Mary K Wojczynski, Jeffrey R O'Connell, May E Montasser, Nicole Schupf, Konstantin Arbeev, Anatoliy Yashin, Nicholas Schork, Kaare Christensen, Stacy L Andersen, Luigi Ferrucci, Noa Rappaport, Thomas T Perls, Gary J Patti.
      Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.
    Keywords:  CP: Metabolism; aging; centenarians; longevity; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114913
  7. Nat Rev Endocrinol. 2024 Nov 05.
    Intricacies and obscurities of non-shivering thermogenesis.
    Anand Kumar Sharma.
      
    DOI:  https://doi.org/10.1038/s41574-024-01060-1
  8. iScience. 2024 Nov 15. 27(11): 111134
    A multiorgan map of metabolic, signaling, and inflammatory pathways that coordinately control fasting glycemia in mice.
    Florence Mehl, Ana Rodríguez Sánchez-Archidona, Ida Meitil, Mathias Gerl, Céline Cruciani-Guglielmacci, Leonore Wigger, Hervé Le Stunff, Kelly Meneyrol, Justine Lallement, Jessica Denom, Christian Klose, Kai Simons, Marco Pagni, Christophe Magnan, Mark Ibberson, Bernard Thorens.
      To identify the pathways that are coordinately regulated in pancreatic β cells, muscle, liver, and fat to control fasting glycemia we fed C57Bl/6, DBA/2, and Balb/c mice a regular chow or a high fat diet for 5, 13, and 33 days. Physiological, transcriptomic and lipidomic data were used in a data fusion approach to identify organ-specific pathways linked to fasting glycemia across all conditions investigated. In pancreatic islets, constant insulinemia despite higher glycemic levels was associated with reduced expression of hormone and neurotransmitter receptors, OXPHOS, cadherins, integrins, and gap junction mRNAs. Higher glycemia and insulin resistance were associated, in muscle, with decreased insulin signaling, glycolytic, Krebs' cycle, OXPHOS, and endo/exocytosis mRNAs; in hepatocytes, with reduced insulin signaling, branched chain amino acid catabolism and OXPHOS mRNAs; in adipose tissue, with increased innate immunity and lipid catabolism mRNAs. These data provide a resource for further studies of interorgan communication in glucose homeostasis.
    Keywords:  Bioinformatics; Omics; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111134
  9. Cell Metab. 2024 Oct 29. pii: S1550-4131(24)00401-7. [Epub ahead of print]
    Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems.
    Ludger J E Goeminne, Anastasiya Vladimirova, Alec Eames, Alexander Tyshkovskiy, M Austin Argentieri, Kejun Ying, Mahdi Moqri, Vadim N Gladyshev.
      Aging is a complex process manifesting at molecular, cellular, organ, and organismal levels. It leads to functional decline, disease, and ultimately death, but the relationship between these fundamental biomedical features remains elusive. By applying elastic net regularization to plasma proteome data of over 50,000 human subjects in the UK Biobank and other cohorts, we report interpretable organ-specific and conventional aging models trained on chronological age, mortality, and longitudinal proteome data. These models predict organ/system-specific disease and indicate that men age faster than women in most organs. Accelerated organ aging leads to diseases in these organs, and specific diets, lifestyles, professions, and medications influence organ aging rates. We then identify proteins driving these associations with organ-specific aging. Our analyses reveal that age-related chronic diseases epitomize accelerated organ- and system-specific aging, modifiable through environmental factors, advocating for both universal whole-organism and personalized organ/system-specific anti-aging interventions.
    Keywords:  aging models; blood plasma; diet; disease; elastic net; lifestyle; longevity interventions; mortality; organ-specific aging; proteomic clocks
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.005
  10. Metabolism. 2024 Nov 03. pii: S0026-0495(24)00287-7. [Epub ahead of print] 156059
    Role of glycogen in cardiac metabolic stress.
    Ke-Fa Xiang, Jing-Jing Wan, Peng-Yuan Wang, Xia Liu.
      Metabolic stress in the myocardium arises from a diverse array of acute and chronic pathophysiological contexts. Glycogen mishandling is a key feature of metabolic stress, while maladaptation in energy-stress situations confers functional deficits. Cardiac glycogen serves as a pivotal reserve for myocardial energy, which is classically described as an energy source and contributes to glucose homeostasis during hypoxia or ischemia. Despite extensive research activity, how glycogen metabolism affects cardiovascular disease remains unclear. In this review, we focus on its regulation across myocardial energy metabolism in response to stress, and its role in metabolism, immunity, and autophagy. We further summarize the cardiovascular-related drugs regulating glycogen metabolism. In this way, we provide current knowledge for the understanding of glycogen metabolism in the myocardium.
    Keywords:  Autophagy; Cardiac glycogen; Glycolysis; Immune regulation; Lipid metabolism; Metabolic stress; Mitochondrial function
    DOI:  https://doi.org/10.1016/j.metabol.2024.156059
  11. Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2412642121
    Quorum sensing orchestrates parallel cell death pathways in Vibrio cholerae via Type 6 secretion-dependent and -independent mechanisms.
    Ameya A Mashruwala, Bonnie L Bassler.
      Quorum sensing (QS) is a cell-to-cell communication process that enables bacteria to coordinate group behaviors. In Vibrio cholerae colonies, a program of spatial-temporal cell death is among the QS-controlled traits. Cell death occurs in two phases, first along the colony rim, and subsequently, at the colony center. Both cell death phases are driven by the type 6 secretion system (T6SS). Here, we show that HapR, the master QS regulator, does not control t6ss gene expression nor T6SS-mediated killing activity. Nonetheless, a ΔhapR strain displays no cell death at the colony rim. RNA-Sequencing (RNA-Seq) analyses reveal that HapR activates expression of an operon containing four genes of unknown function, vca0646-0649. Epistasis and overexpression studies show that two of the genes, vca0646 and vca0647, are required to drive cell death in both a ΔhapR and a ΔhapR Δt6ss strain. Thus, vca0646-0649 are regulated by HapR but act independently of the T6SS machinery to cause cell death, suggesting that a second, parallel pathway to cell death exists in V. cholerae.
    Keywords:  Vibrio cholerae; quorum sensing; regulated cell death; type 6 secretion
    DOI:  https://doi.org/10.1073/pnas.2412642121
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