bims-endanx Biomed News
on Endocrine Anxiety
Issue of 2025–03–09
eight papers selected by
Logan K. Townsend, McMaster University
  1. Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
  2. A cellular and molecular basis of leptin resistance.
  3. Altered liver lipidome markedly overlaps with human plasma lipids at diabetes risk and reveals adipose-liver interaction.
  4. "Shunt-ing" down obesity with novel endogenous metabolites.
  5. More strain, more brain: the impact of exercise intensity on neurogenesis.
  6. SnapShot: Brain-targeting anti-obesity medications.
  7. Metabolic dysfunction-associated steatotic liver disease in adults.
  8. Integrative Metabolism in MASLD and MASH: Pathophysiology and Emerging Mechanisms.
  1. Nat Metab. 2025 Mar 06.
    Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
    Trine S Nicolaisen, Aslak E Lyster, Kim A Sjøberg, Daniel T Haas, Christian T Voldstedlund, Anne-Marie Lundsgaard, Jakob K Jensen, Ea M Madsen, Casper K Nielsen, Mads Bloch-Ibenfeldt, Nicolai J Wewer Albrechtsen, Adam J Rose, Natalie Krahmer, Christoffer Clemmensen, Erik A Richter, Andreas M Fritzen, Bente Kiens.
      Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.
    DOI:  https://doi.org/10.1038/s42255-025-01236-7
  2. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00001-4. [Epub ahead of print]37(3): 723-741.e6
    A cellular and molecular basis of leptin resistance.
    Bowen Tan, Kristina Hedbacker, Leah Kelly, Zhaoyue Zhang, Alexandre Moura-Assis, Ji-Dung Luo, Joshua D Rabinowitz, Jeffrey M Friedman.
      Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling. Rapamycin restored leptin's actions on POMC neurons and failed to reduce the weight of mice with defects in melanocortin signaling. mTOR activation in POMC neurons caused leptin resistance, whereas POMC-specific mutations in mTOR activators decreased weight gain of DIO mice. Thus, increased mTOR activity in POMC neurons is necessary and sufficient for the development of leptin resistance in DIO mice, establishing a key pathogenic mechanism leading to obesity.
    Keywords:  POMC; diet-induced obesity; leptin; leptin resistance; mTOR; rapamycin
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.001
  3. J Lipid Res. 2025 Mar 03. pii: S0022-2275(25)00027-6. [Epub ahead of print] 100767
    Altered liver lipidome markedly overlaps with human plasma lipids at diabetes risk and reveals adipose-liver interaction.
    Ratika Sehgal, Markus Jähnert, Michail Lazaratos, Thilo Speckmann, Fabian Schumacher, Burkhard Kleuser, Meriem Ouni, Wenke Jonas, Annette Schürmann.
      Present study explores the role of liver lipidome in driving T2D-associated metabolic changes. Elevated liver triacylglycerols, reduced PUFAs, and 86 differentially abundant lipid species were identified in diabetes-prone mice. Of these altered lipid species 82 markedly overlap with human plasma lipids associated with T2D/CVD risk. Pathway enrichment highlighted sphingolipid metabolism, however, only five of all genes involved in the pathway were differentially expressed in the liver. Interestingly, overlap with adipose tissue transcriptome was much higher (57 genes), pointing towards an active adipose-liver interaction. Next, the integration of liver lipidome and transcriptome identified strongly correlated lipid-gene networks highlighting Cer(22:0), dCer(24:1), and TAG(58:6) playing a central role in transcriptional regulation. Putative molecular targets of Cer(22:0) were altered (Cyp3a44, Tgf-β1) in primary mouse hepatocytes treated with Cer(22:0). Early alteration of liver lipidome markedly depends on adipose tissue expression pattern and provides substantial evidence linking early liver lipidome alterations and risk of T2D.
    Keywords:  Lipid species; New Zealand Obese mice; Obesity; Type 2 diabetes; diabetes-prone/resistant
    DOI:  https://doi.org/10.1016/j.jlr.2025.100767
  4. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00063-4. [Epub ahead of print]37(3): 564-565
    "Shunt-ing" down obesity with novel endogenous metabolites.
    Victor J Pai, Alan Saghatelian.
      Obesity is a growing public health issue that has recently been transformed through the advent of new medicines. However, our understanding of the pathways and mechanisms that regulate energy balance in mammals is still developing. Recent discoveries on this front include an exciting new finding that there exists a novel class of metabolites in humans and mice that can regulate obesity in rodents.
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.005
  5. J Physiol. 2025 Mar 03.
    More strain, more brain: the impact of exercise intensity on neurogenesis.
    Federico Picciau, Valdemar Brimnes Ingemann Johansen, Christoffer Merrild.
      
    Keywords:  forced treadmill running; high‐intensity interval training (HIIT); hippocampus; hydroxycarboxylic acid receptor 1 (HCA1); lactate; medium‐intensity interval training (MIIT); neurogenesis; ventricular–subventricular zone
    DOI:  https://doi.org/10.1113/JP288408
  6. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00064-6. [Epub ahead of print]37(3): 790-790.e1
    SnapShot: Brain-targeting anti-obesity medications.
    Jonas Petersen, Valdemar Brimnes Ingemann Johansen, Christoffer Clemmensen.
      Advances in the understanding of homeostatic regulation of body weight and the neurobiology of appetite, combined with innovations in medicinal chemistry, have paved the way for safe and effective weight loss medications. Long-acting GLP-1 receptor agonists have revolutionized obesity treatment, and, together with emerging GLP-1-based multi-agonists and combination therapies, offer significant potential to combat cardiometabolic diseases and a range of other chronic health challenges. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.006
  7. Nat Rev Dis Primers. 2025 Mar 06. 11(1): 15
    Metabolic dysfunction-associated steatotic liver disease in adults.
      
    DOI:  https://doi.org/10.1038/s41572-025-00604-7
  8. J Hepatol. 2025 Mar 01. pii: S0168-8278(25)00142-4. [Epub ahead of print]
    Integrative Metabolism in MASLD and MASH: Pathophysiology and Emerging Mechanisms.
    Gregory R Steinberg, Celina M Valvano, William De Nardo, Matthew J Watt.
      The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, and amino acid metabolism. Gut-derived metabolites, such as acetate and ethanol and non-esterified fatty acids from white adipose tissue (WAT), influence hepatic processes, which rely on mitochondrial function to maintain systemic energy balance. Metabolic dysregulation from obesity, insulin resistance, and type 2 diabetes disrupt these pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). This review explores the metabolic fluxes within the gut-adipose tissue-liver axis, focusing on the pivotal role of de novo lipogenesis (DNL), dietary substrates like glucose and fructose, and changes in mitochondrial function during MASLD progression. It highlights the contributions of white adipose tissue insulin resistance and impaired mitochondrial dynamics to hepatic lipid accumulation. Further understanding how the interplay between substrate flux from the gastro-intestinal tract integrates with adipose tissue and intersects with structural and functional alterations to liver mitochondria will be important to identify novel therapeutic targets and advance the treatment of MASLD and MASH.
    Keywords:  AMPK; acetate; denovo lipogenesis; fructose; gut-liver axis; insulin resistance; lactate; lipolysis; mitophagy; subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT)
    DOI:  https://doi.org/10.1016/j.jhep.2025.02.033
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒09 at 15:45.