bims-mimead 2024-12-15 papers

Issue of 2024–12–15
seven papers selected by
Rachel M. Handy, University of Guelph

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

FASEB J. 2024 Dec 15. 38(23): e70254

PFKFB3 protein in adipose tissue contributes to whole body glucose homeostasis.

Beth A Griesel, Ann Louise Olson.

Age-dependent changes in adipose tissue are thought to play a role in development of insulin resistance. A major age-dependent change in adipose tissue is the downregulation of key proteins involved in carbohydrate metabolism. In the current study, we investigate the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) a key governor of the rate of glycolysis in adipocytes via the synthesis of fructose-2,6-bisphosphate that was significantly downregulated in aged mice. We employed an adipocyte-specific PFKFB3 mouse line to investigate the role of PFKFB3 on adipocyte function. In both aged mice and PFKFB3-knockout mice, we observed an increase in O-glcNAcylated proteins consistent with a shift in glucose metabolism toward the hexosamine biosynthetic pathway. Under chow-fed conditions, PFKFB3 knockout resulted in significantly smaller adipocyte area, but no difference in total fat mass. While glucose tolerance was unchanged under chow conditions, when mice were challenged with a 4 weeks high-fat feeding, PFKFB3 deletion led to a greater decrease in glucose tolerance as well as a significant increase in macrophage infiltration. These results indicate that perturbation of the glycolytic pathway in adipose tissue has multiple effects of adipocyte biology and may play a significant role in metabolic changes associated with aging. Results of this student support the notion that changes in glucose metabolism in adipose tissue impact whole-body metabolism.

Keywords: O‐glcNAcylation; PFKFB3; adipose; aging; glucose homeostasis

DOI: https://doi.org/10.1096/fj.202402070R

Mol Metab. 2024 Dec 08. pii: S2212-8778(24)00212-6. [Epub ahead of print] 102081

Exercise-Induced Methylation of the Serhl2 Promoter and Implication for Lipid Metabolism in Rat Skeletal Muscle.

Mutsumi Katayama, Kazuhiro Nomura, Jonathan M Mudry, Alexander V Chibalin, Anna Krook, Juleen R Zierath.

OBJECTIVE: Environmental factors such as physical activity induce epigenetic modification, with exercise-responsive DNA methylation changes occurring in skeletal muscle. To determine the skeletal muscle DNA methylation signature to endurance swim training we used whole-genome methylated DNA immunoprecipitation (MeDIP) sequencing.
RESULTS: Gene set expression analysis (GSEA) of differentially methylated promoter regions (DMRs) an enrichment of four gene sets, including those annotated to lipid metabolic process, with differentially hypermethylated or hypomethylated promoter regions in skeletal muscle of exercise-trained rats. Single base resolution bisulfite sequencing confirmed that neighboring CpGs in the transcription start site of Serhl2 (Serine Hydrolase Like 2) were hypomethylated in exercise-trained rats. Serhl2 gene expression was upregulated in exercise-trained rats, as well as in an exercise-in-a-dish model of L6 myotubes subjected to electrical pulse stimulation (EPS). Serhl2 promoter activity was regulated by methylation, and in response to EPS. We identified a Nr4a binding motif in the Serhl2 promoter region, which upon deletion, reduced Serhl2 promoter activity and abolished sensitivity to methylation in L6 myotubes. Gene silencing of Serhl2 in L6 myotubes reduced both intracellular lipid oxidation and triacylglycerol synthesis in response to EPS.
CONCLUSION: Exercise training promotes intracellular lipid metabolism and phenotypic changes in skeletal muscle through epigenomic modifications on Serine Hydrolase Like 2. Hypomethylation of Serhl2 promoter affects transcription factor binding of Nr4a, Serhl2 promoter activity, and Serhl2 mRNA expression in skeletal muscle. Our data link exercise-induced epigenomic regulation Serhl2 with lipid oxidation and triacylglycerol synthesis in skeletal muscle.

Keywords: DNA methylation; Exercise training; Lipid metabolism; Promoter activity; Serine hydrolase like 2; Skeletal muscle

DOI: https://doi.org/10.1016/j.molmet.2024.102081

Nat Aging. 2024 Dec;4(12): 1731-1744

Exploring the effects of estrogen deficiency and aging on organismal homeostasis during menopause.

Celine Camon, Michael Garratt, Stephanie M Correa.

Sex hormone signaling declines during aging, from early midlife through menopause, as a consequence of reduced circulating estrogens and decreased receptiveness to these hormones in target tissues. Estrogens preserve energy homeostasis and promote metabolic health via coordinated and simultaneous effects throughout the brain and body. Age-associated loss of estrogen production during menopause has been implicated in a higher risk for metabolic diseases and increased mortality. However, it remains unclear whether age-associated changes in homeostasis are dependent on reduced estrogen signaling during menopause. Although menopausal hormone therapies containing estrogens can alleviate symptoms, concerns about the risks involved have contributed to a broad decline in the use of these approaches. Non-hormonal therapies have emerged that target tissues or pathways with varying levels of selectivity, reducing risk. We summarize here the broad effects of estrogen loss on homeostasis during menopause, current and emerging therapies and opportunities for understanding homeostatic disruptions associated with menopause.

DOI: https://doi.org/10.1038/s43587-024-00767-0

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