bims-mimead 2025-03-09 papers

Issue of 2025–03–09
six papers selected by
Rachel M. Handy, University of Guelph

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

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

Mol Metab. 2025 Mar 01. pii: S2212-8778(25)00026-2. [Epub ahead of print] 102119

Apolipoprotein A-IV is induced by high-fat diets and mediates positive effects on glucose and lipid metabolism.

Anne-Marie Lundsgaard, Rita Del Giudice, Josephine M Kanta, Mark Larance, Sarah L Armour, Amalie London, Michael M Richter, Nicoline R Andersen, Trine S Nicolaisen, Christian S Carl, Kim A Sjøberg, Kirstine Nyvold Bojsen-Møller, Jakob G Knudsen, Jens O Lagerstedt, Andreas M Fritzen, Bente Kiens.

BACKGROUND: Low-carbohydrate, high-fat diets under eucaloric conditions are associated with several health-beneficial metabolic effects in humans, particularly in the liver. We recently observed that apolipoprotein A-IV (apoA-IV), a highly abundant apolipoprotein, was among the most upregulated proteins in circulation after six weeks of consuming a high-fat diet in humans. However, the impact of dietary changes in regulating apoA-IV, and the potential effects of apoA-IV on regulation of glucose- and lipid metabolism remain to be fully established.
RESULTS: We demonstrate that in healthy human individuals high-fat intake increased fasting plasma apoA-IV concentrations by up to 54%, while high-carbohydrate intake suppressed plasma apoA-IV concentrations. In mice, administration of apoA-IV acutely lowered blood glucose levels both in lean and obese mice. Interestingly, this was related to a dual mechanism, involving both inhibition of hepatic glucose production and increased glucose uptake into white and brown adipose tissues. In addition to an effect on hepatic glucose production, the apoA-IV-induced liver proteome revealed increased capacity for lipoprotein clearance. The effects of apoA-IV in the liver and adipose tissues were concomitant with increased whole-body fatty acid oxidation. Upon glucose stimulation, an improvement in glucose tolerance by apoA-IV administration was related to potentiation of glucose-induced insulin secretion, while apoA-IV inhibited glucagon secretion ex vivo in islets.
CONCLUSION: We find that apoA-IV is potently increased by intake of fat in humans, and that several beneficial metabolic effects, previously associated with high fat intake in humans, are mimicked by administration of apoA-IV protein to mice.

Keywords: Chylomicron; adipose tissue; diet; fatty acid oxidation; hepatic glucose production; incretin hormone; insulin secretion; liver

DOI: https://doi.org/10.1016/j.molmet.2025.102119

Adipocyte. 2025 Dec;14(1): 2474114

miR-6402 targets Bmpr2 and negatively regulates mouse adipogenesis.

Malaz Elsheikh, Tomomi Sano, Akiko Mizokami, Yusuke Nakatsu, Tomoichiro Asano, Takashi Kanematsu.

Obesity is characterized by macrophage infiltration into adipose tissue. White adipose tissue remodelling under inflammatory conditions involves both hypertrophy and adipogenesis and is regulated by transcription factors, which are influenced by bone morphogenetic protein (BMP) signalling. MicroRNAs (miRNAs) regulate gene expression and are involved in obesity-related processes such as adipogenesis. Therefore, we identified differentially expressed miRNAs in the epididymal white adipose tissue (eWAT) of mice fed a normal diet (ND) and those fed a high-fat diet (HFD). The expression of miR-6402 was significantly suppressed in the inflamed eWAT of HFD-fed mice than in ND-fed mice. Furthermore, Bmpr2, the receptor for BMP4, was identified as a target gene of miR-6402. Consistently, miR-6402 was downregulated in the inflamed eWAT of HFD-fed mice and in 3T3-L1 cells (preadipocytes) and differentiated 3T3-L1 cells (mature adipocytes) , and BMPR2 expression in these cells was upregulated. Adipogenesis was induced in WAT by BMP4 injection (in vivo) and in 3T3-L1 cells by BMP4 stimulation (in vitro), both of which were inhibited by miR-6402 transfection. Inflamed eWAT showed higher expression of BMPR2 and the adipogenesis markers C/EBPβ and PPARγ, which was suppressed by miR-6402 transfection. Our findings suggest that miR-6402 is a novel anti-adipogenic miRNA that combats obesity by inhibiting the BMP4/BMPR2 signalling pathway and subsequently reducing adipose tissue expansion.

Keywords: Adipocyte; adipogenesis; bone morphogenetic protein receptor type 2; miR-6402; microRNA

DOI: https://doi.org/10.1080/21623945.2025.2474114

Commun Med (Lond). 2025 Mar 03. 5(1): 56

Deep proteome profiling of metabolic dysfunction-associated steatotic liver disease.

Felix Boel, Vyacheslav Akimov, Mathias Teuchler, Mike Krogh Terkelsen, Charlotte Wilhelmina Wernberg, Frederik Tibert Larsen, Philip Hallenborg, Mette Munk Lauridsen, Aleksander Krag, Susanne Mandrup, Kim Ravnskjær, Blagoy Blagoev.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 1 in 3 adults and is a leading cause of liver transplants and liver related mortality. A deeper understanding of disease pathogenesis is essential to assist in developing blood-based biomarkers.
METHODS: Here, we use data-independent acquisition mass spectrometry to assess disease-state associated protein profiles in human liver, blood plasma, and white adipose tissue (WAT).
RESULTS: In liver, we find that MASLD is associated with an increased abundance of proteins involved in immune response and extracellular matrix (ECM) and a decrease in proteins involved in metabolism. Cell type deconvolution of the proteome indicates liver endothelial and hepatic stellate cells are the main source of ECM rearrangements, and hepatocytes are the major contributor to the changes in liver metabolism. In the blood, profiles of several MASLD-associated proteins correlate with expression in WAT rather than liver and so could serve as suitable liver disease predictors in a multi-protein panel marker. Moreover, our proteomics-based logistic regression models perform better than existing methods for predicting MASLD and liver fibrosis from human blood samples.
CONCLUSIONS: Our comprehensive proteomic analysis deepens the understanding of liver function and MASLD pathology by elucidating key cellular mechanisms and multi-organ interactions, and demonstrates the robustness of a proteomics-based biomarker panel to enhance diagnosis of MASLD and significant fibrosis.

DOI: https://doi.org/10.1038/s43856-025-00780-3

Diabetes. 2025 Feb 28. pii: db241003. [Epub ahead of print]

Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2.

Jeongmin Lee, Alessandro Ustione, Emily M Wilkerson, Rekha Balakrishnan, Debbie C Thurmond, Dennis Goldfarb, David W Piston.

Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrate the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D model, nonobese diabetic (NOD) mice, by suppressing glucagon secretion. This fraction promotes white adipocyte differentiation and browning, maintains healthy BAT, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. We identify nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. Secretions from a BAT cell line with siRNA knockdown of nidogen-2 fail to inhibit glucagon secretion and restore euglycemia. These findings demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2, beyond its traditional classification as an extracellular matrix protein.

DOI: https://doi.org/10.2337/db24-1003