bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–12–15
eight papers selected by
Henver Brunetta, Karolinska Institutet
  1. The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice.
  2. Adipose tissue biology and effect of weight loss in women with lipedema.
  3. Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner.
  4. Decreased Adipose Lipid Turnover Associates With Cardiometabolic Risk and the Metabolic Syndrome.
  5. Cold acclimation with shivering improves metabolic health in adults with overweight or obesity.
  6. Lipidome profiling in advanced metabolic liver disease identifies phosphatidylserine synthase 1 as a regulator of hepatic lipoprotein metabolism.
  7. ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools.
  8. Reactive oxygen species control protein degradation at the mitochondrial import gate.
  1. Cell Metab. 2024 Dec 04. pii: S1550-4131(24)00449-2. [Epub ahead of print]
    The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice.
    Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Valentina Pirro, Margo P Emont, Brian A Droz, Kyla Ai Collins, Chanmin Joung, Mackenzie J Pearson, Corey M James, Gopal J Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu A An, Evan D Rosen, Matthew P Coghlan, Ricardo J Samms, Philipp E Scherer, Christine M Kusminski.
      Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance.
    Keywords:  GIP receptor; SERCA pathway; adipose tissue; energy expenditure; obesity; weight loss
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.003
  2. Diabetes. 2024 Dec 09. pii: db240890. [Epub ahead of print]
    Adipose tissue biology and effect of weight loss in women with lipedema.
    Vincenza Cifarelli, Gordon I Smith, Silvia Gonzalez-Nieves, Dmitri Samovski, Hector H Palacios, Jun Yoshino, Richard I Stein, Anja Fuchs, Thomas F Wright, Samuel Klein.
      Lipedema is a lipodystrophic disease that is typically characterized by a marked increase in lower-body subcutaneous adipose tissue that is purported to have increased inflammation and fibrosis, impaired microvascular/lymphatic circulation and to be resistant to reduction by weight loss therapy. However, these outcomes have not been adequately studied. We evaluated body composition, insulin sensitivity, metabolic health and adipose tissue biology in women with obesity and lipedema (Obese-LIP) before and after moderate (~9%) diet-induced weight loss. At baseline, people with Obese-LIP had ~23% greater leg fat mass, ~11% lower android-to-gynoid ratio and ~48% greater insulin sensitivity (all P<0.05) than women matched on age, BMI and whole-body adiposity. In Obese-LIP, macrophage content and expression of genes involved in inflammation and fibrosis were greater, whereas lymph/angiogenesis-related genes were lower in thigh than abdominal subcutaneous adipose tissue. Weight loss improved insulin sensitivity and decreased total fat mass, with similar relative reductions in abdominal and leg fat masses, but without changes in markers of inflammation and fibrosis. These results demonstrate that affected adipose tissue in women with lipedema is characterized by increased inflammation and fibrogenesis, and alterations in lymphatic and vascular biology. Moderate diet-induced weight loss improves metabolic function and decreases lower-body adipose tissue mass.
    DOI:  https://doi.org/10.2337/db24-0890
  3. Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01357-3. [Epub ahead of print]43(12): 115006
    Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner.
    Joseph Choi, Danielle M Smith, Susanna Scafidi, Ryan C Riddle, Michael J Wolfgang.
      Mitochondrial fatty acid oxidation is facilitated by the combined activities of carnitine palmitoyltransferase 1 (Cpt1) and Cpt2, which generate and utilize acylcarnitines, respectively. We compare the response of mice with liver-specific deficiencies in the liver-enriched Cpt1a or the ubiquitously expressed Cpt2 and discover that they display unique metabolic, physiological, and molecular phenotypes. The loss of Cpt1a or Cpt2 results in the induction of the muscle-enriched isoenzyme Cpt1b in hepatocytes in a Pparα-dependent manner. However, hepatic Cpt1b does not contribute substantively to hepatic fatty acid oxidation when Cpt1a is absent. Liver-specific double knockout of Cpt1a and Cpt1b or Cpt2 eliminates the mitochondrial oxidation of non-esterified fatty acids. However, Cpt1a/Cpt1b double knockout mice retain fatty acid oxidation by utilizing extracellular long-chain acylcarnitines that are dependent on Cpt2. These data demonstrate the non-cell-autonomous intercellular metabolism of fatty acids in hepatocytes.
    Keywords:  CP: Metabolism; Cpt1; Cpt2; acylcarnitine; biochemistry; fasting; liver; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.115006
  4. Arterioscler Thromb Vasc Biol. 2024 Dec 12.
    Decreased Adipose Lipid Turnover Associates With Cardiometabolic Risk and the Metabolic Syndrome.
    Daniel P Andersson, Peter Arner.
       BACKGROUND: Disturbed white adipose tissue function is important for cardiometabolic risk and metabolic syndrome (MetS). Whether this involves adipose lipid turnover (lipolysis and synthesis of triglycerides) is unknown and was presently investigated in subcutaneous adipose tissue, the body's largest fat depot.
    METHODS: In cross-sectional studies in 78 subjects, adipose lipid age, representing overall lipid turnover (mobilization and storage), and lipid storage capacity were assessed by the incorporation of atmospheric 14C into adipose lipids. Adipose lipid age from an algorithm of adipocyte lipolysis and clinical parameters was also determined in 185 subjects. Adult Treatment Panel III (ATPIII) scoring defined MetS (scores 3-5) or healthy (score 0). ANOVA or ANCOVA and t test were used for statistical comparison. Because there was no method interaction to determine lipid age, the 2 groups were combined.
    RESULTS: Lipid age increased by incremental ATPIII score (F=42; P<0.0001) and was 2-fold advanced in MetS (t=11.3; P<0.0001). The correlation with lipid age was independent of age, sex, body mass index, waist-to-hip ratio, sedentary lifestyle, absence of obesity, and adipose insulin resistance (F=10.7; P<0.0001). Lipid storage capacity was not related to the ATPIII score (F=1.0; P=0.44) or MetS (t=-0.9; P=0.35). Adipocyte lipolysis activation was decreased in MetS and inversely related to incremental ATPIII score, suggesting that decreased lipid mobilization is the major factor behind high lipid age in these conditions.
    CONCLUSIONS: Despite normal lipid assimilation capacity, abdominal subcutaneous adipose lipid turnover is decreased in MetS and high ATPIII score because of impaired ability to mobilize lipids involving low adipocyte lipolysis activation.
    Keywords:  adipocytes; insulin resistance; lipolysis; obesity; triglycerides
    DOI:  https://doi.org/10.1161/ATVBAHA.124.321760
  5. Nat Metab. 2024 Dec 06.
    Cold acclimation with shivering improves metabolic health in adults with overweight or obesity.
    Adam J Sellers, Sten M M van Beek, Dzhansel Hashim, Rosalie Baak, Hannah Pallubinsky, Esther Moonen-Kornips, Gert Schaart, Anne Gemmink, Johanna A Jörgensen, Tineke van de Weijer, Eric Kalkhoven, Guido J Hooiveld, Sander Kersten, Matthijs K C Hesselink, Patrick Schrauwen, Joris Hoeks, Wouter D van Marken Lichtenbelt.
      Cold acclimation increases insulin sensitivity, and some level of muscle contraction appears to be needed for provoking this effect. Here 15 men and (postmenopausal) women with overweight or obesity, the majority of whom had impaired glucose tolerance, were intermittently exposed to cold to induce 1 h of shivering per day over 10 days. We determined the effect of cold acclimation with shivering on overnight fasted oral glucose tolerance (primary outcome) and on skeletal muscle glucose transporter 4 translocation (secondary outcome). We find that cold acclimation with shivering improves oral glucose tolerance, fasting glucose, triglycerides, non-esterified fatty acid concentrations and blood pressure. Cold acclimation with shivering may thus represent an alternative lifestyle approach for the prevention and treatment of obesity-related metabolic disorders. ClinicalTrials.gov registration: NCT04516018 .
    DOI:  https://doi.org/10.1038/s42255-024-01172-y
  6. Cell Rep. 2024 Dec 11. pii: S2211-1247(24)01358-5. [Epub ahead of print]43(12): 115007
    Lipidome profiling in advanced metabolic liver disease identifies phosphatidylserine synthase 1 as a regulator of hepatic lipoprotein metabolism.
    Marziyeh Anari, Hamzeh Karimkhanloo, Shuai Nie, Li Dong, Gio Fidelito, Jacqueline Bayliss, Stacey N Keenan, John Slavin, Sihan Lin, Zhili Cheng, Jie Lu, Paula M Miotto, William De Nardo, Camille J Devereux, Nicholas A Williamson, Matthew J Watt, Magdalene K Montgomery.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by defective lipid metabolism, which causes disease progression. MASH is also linked to various cardiometabolic risk factors, including obesity and type 2 diabetes. The contribution of defective lipid metabolism in MASH to cardiometabolic comorbidities is incompletely understood. Using hepatic lipidome profiling in eight mouse strains that differ in MASH susceptibility and patients with MASH, we show that phosphatidylserine (PS) accumulation and preservation of PS synthase 1 (PSS1) expression is associated with resistance to MASH and hypertriglyceridemia. Mechanistically, hepatocyte-specific PSS1 overexpression remodels the hepatic and very-low-density lipoprotein (VLDL) lipidome in mice with MASH. Specifically, we show an increase in VLDL ceramide that suppresses the expression and activity of lipoprotein lipase in skeletal muscle, thereby reducing VLDL-triglyceride clearance, fatty acid uptake, and lipid accumulation in muscle, overall exacerbating hypertriglyceridemia. Together, the results of this study identify hepatic PSS1 as a regulator of systemic lipoprotein metabolism.
    Keywords:  CP: Metabolism; ceramide; lipid metabolism; lipoprotein lipase; phospholipid; tissue communication; very low-density lipoprotein
    DOI:  https://doi.org/10.1016/j.celrep.2024.115007
  7. Sci Transl Med. 2024 Dec 11. 16(777): eadi6682
    ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools.
    Veronica D Dahik, Pukar Kc, Clément Materne, Canelle Reydellet, Marie Lhomme, Céline Cruciani-Guglielmacci, Jessica Denom, Eric Bun, Maharajah Ponnaiah, Florence Deknuydt, Eric Frisdal, Lise M Hardy, Hervé Durand, Isabelle Guillas, Philippe Lesnik, Ivan Gudelj, Gordan Lauc, Maryse Guérin, Anatol Kontush, Antoine Soprani, Christophe Magnan, Marc Diedisheim, Olivier Bluteau, Nicolas Venteclef, Wilfried Le Goff.
      The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.
    DOI:  https://doi.org/10.1126/scitranslmed.adi6682
  8. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00909-2. [Epub ahead of print]84(23): 4612-4628.e13
    Reactive oxygen species control protein degradation at the mitochondrial import gate.
    Rachael McMinimy, Andrew G Manford, Christine L Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y Shih, Christopher M Rose, John Kuriyan, Baris Bingol, Michael Rapé.
      While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2FEM1B), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.
    Keywords:  FEM1B; TOM complex; electron transport chain; mitochondria; proteasome; reductive stress response; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.004
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