bims-obesme Biomed News
on Obesity metabolism
Issue of 2024‒05‒19
fourteen papers selected by
Xiong Weng, University of Edinburgh
  1. Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
  2. linc-ADAIN, a human adipose lincRNA, regulates adipogenesis by modulating KLF5 and IL-8 mRNA stability.
  3. Immunity in adipose tissues: Cutting through the fat.
  4. MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.
  5. Suppression of hepatic ChREBP⍺-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH.
  6. SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL.
  7. Transcriptional and hormonal control of adipose Treg heterogeneity and function.
  8. Serine synthesis controls mitochondrial biogenesis in macrophages.
  9. Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.
  10. Mitochondria targeted esculetin administration improves insulin resistance and hyperglycemia-induced atherosclerosis in db/db mice.
  11. The role of brown adipose tissue in metabolic health.
  12. LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.
  13. AMPK as a mediator of tissue preservation: time for a shift in dogma?
  14. Impact of Plant-Based Dietary Fibers on Metabolic Homeostasis in High-Fat Diet Mice via Alterations in the Gut Microbiota and Metabolites.
  1. Nat Commun. 2024 May 17. 15(1): 4214
    Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
    Dongliang Lu, Anyuan He, Min Tan, Marguerite Mrad, Amal El Daibani, Donghua Hu, Xuejing Liu, Brian Kleiboeker, Tao Che, Fong-Fu Hsu, Monika Bambouskova, Clay F Semenkovich, Irfan J Lodhi.
      The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-48471-2
  2. Cell Rep. 2024 May 14. pii: S2211-1247(24)00568-0. [Epub ahead of print]43(5): 114240
    linc-ADAIN, a human adipose lincRNA, regulates adipogenesis by modulating KLF5 and IL-8 mRNA stability.
    Marcella E O'Reilly, Sebastian Ho, Johana Coronel, Lucie Zhu, Wen Liu, Chenyi Xue, Eunyoung Kim, Esther Cynn, Caio V Matias, Rajesh Kumar Soni, Chen Wang, Iuliana Ionita-Laza, Robert C Bauer, Leila Ross, Yiying Zhang, Silvia Corvera, Susan K Fried, Muredach P Reilly.
      Adipose tissue remodeling and dysfunction, characterized by elevated inflammation and insulin resistance, play a central role in obesity-related development of type 2 diabetes (T2D) and cardiovascular diseases. Long intergenic non-coding RNAs (lincRNAs) are important regulators of cellular functions. Here, we describe the functions of linc-ADAIN (adipose anti-inflammatory), an adipose lincRNA that is downregulated in white adipose tissue of obese humans. We demonstrate that linc-ADAIN knockdown (KD) increases KLF5 and interleukin-8 (IL-8) mRNA stability and translation by interacting with IGF2BP2. Upregulation of KLF5 and IL-8, via linc-ADAIN KD, leads to an enhanced adipogenic program and adipose tissue inflammation, mirroring the obese state, in vitro and in vivo. KD of linc-ADAIN in human adipose stromal cell (ASC) hTERT adipocytes implanted into mice increases adipocyte size and macrophage infiltration compared to implanted control adipocytes, mimicking hallmark features of obesity-induced adipose tissue remodeling. linc-ADAIN is an anti-inflammatory lincRNA that limits adipose tissue expansion and lipid storage.
    Keywords:  CP: Metabolism; CP: Molecular biology; HuR; IGF2BP2; IL-8; KLF5; adipogenesis; linc-ADAIN; linc-DMRT2; linc01230; long non-coding RNA; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2024.114240
  3. Immunol Rev. 2024 May 11.
    Immunity in adipose tissues: Cutting through the fat.
    Troy D Randall, Selene Meza-Perez.
      Well known functions of adipose tissue include energy storage, regulation of thermogenesis, and glucose homeostasis-each of which are associated with the metabolic functions of fat. However, adipose tissues also have important immune functions. In this issue of Immunological Reviews, we present a series of articles that highlight the immune functions of adipose tissue, including the roles of specialized adipose-resident immune cells and fat-associated lymphoid structures. Importantly, immune cell functions in adipose tissues are often linked to the metabolic functions of adipocytes and vice versa. These reciprocal interactions and how they influence both immune and metabolic functions will be discussed in each article. In the first article, Wang et al.,11 discuss adipose-associated macrophages and how obesity and metabolism impact their phenotype and function. Several articles in this issue discuss T cells as either contributors to, or regulators of, inflammatory responses in adipose tissues. Valentine and Nikolajczyk12 provide insights into the role of T cells in obesity-associated inflammation and their contribution to metabolic dysfunction, whereas an article from Kallies and Vasanthakumar13 and another from Elkins and Li14 describe adipose-associated Tregs and how they help prevent inflammation and maintain metabolic homeostasis. Articles from Okabe35 as well as from Daley and Benezech15 discuss the structure and function of fat-associated lymphoid clusters (FALCs) that are prevalent in some adipose tissues and support local immune responses to pathogens, gut-derived microbes and fat-associated antigens. Finally, an article from Meher and McNamara16 describes how innate-like B1 cells in adipose tissues regulate cardiometabolic disease. Importantly, these articles highlight the physical and functional attributes of adipose tissues that are different between mice and humans, the metabolic and immune differences between various adipose depots in the body and the differences in immune cells, adipose tissues and metabolic functions between the sexes. At the end of this preface, we highlight how these differences are critically important for our understanding of anti-tumor immunity to cancers that metastasize to a specific example of visceral adipose tissue, the omentum. Together, these articles identify some unanswered mechanistic questions that will be important to address for a better understanding of immunity in adipose tissues.
    Keywords:  adipose tissue; adipose‐resident T cells; fat‐associated lymphoid cluster; obesity; omentum
    DOI:  https://doi.org/10.1111/imr.13344
  4. Biol Res. 2024 May 14. 57(1): 27
    MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.
    Shaheen Wasil Kabeer, Shivam Sharma, Shalemraju Sriramdasu, Kulbhushan Tikoo.
      BACKGROUND: Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance.RESULTS: Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1-6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1-6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1-6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis.
    CONCLUSION: Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases.
    Keywords:  Epigenetic regulation; FOXO1; Gluconeogenesis; Insulin resistance; miR-721
    DOI:  https://doi.org/10.1186/s40659-024-00495-0
  5. Mol Metab. 2024 May 11. pii: S2212-8778(24)00088-7. [Epub ahead of print] 101957
    Suppression of hepatic ChREBP⍺-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH.
    Deqiang Zhang, Yuee Zhao, Gary Zhang, Daniel Lank, Sarah Cooke, Sujuan Wang, Alli Nuotio-Antar, Xin Tong, Lei Yin.
      Compromised hepatic fatty acid oxidation (FAO) has been observed in human MASH patients and animal models of MASLD/MASH. It remains poorly understood how and when the hepatic FAO pathway is suppressed during the progression of MASLD towards MASH. Hepatic ChREBP⍺ is a classical lipogenic transcription factor that responds to the intake of dietary sugars. We examined its role in regulating hepatocyte fatty acid oxidation (FAO) and the impact of hepatic Chrebpa deficiency on sensitivity to diet-induced MASLD/MASH in mice. We discovered that hepatocyte ChREBP⍺ is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPAR⍺/δ agonist is sufficient to restore FAO in Chrebp-/- primary murine hepatocytes. Hepatic ChREBP⍺ was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp⍺ knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBP⍺-WT or its non-lipogenic mutant enhanced FAO, reduced lipid deposition, and alleviated liver injury, inflammation, and fibrosis. RNA-seq analysis identified the CYP450 epoxygenase (CYP2C50) pathway of arachidonic acid metabolism as a novel target of ChREBP⍺. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp⍺ deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebp⍺-deleted mice. Thus, our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.
    Keywords:  Carbohydrate-Response Element Binding Protein (ChREBP); Fatty acid oxidation; Lipid metabolism; Non-Alcoholic Steatohepatitis
    DOI:  https://doi.org/10.1016/j.molmet.2024.101957
  6. J Diabetes Res. 2024 ;2024 5511454
    SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL.
    Hua Guan, Lin Xiao, Kaikai Hao, Qiang Zhang, Dongliang Wu, Zhanyi Geng, Bowen Duan, Hui Dai, Ruifen Xu, Xuyang Feng.
      Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1α. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.
    Keywords:  SLC25A28/mitoferrin 2; adipose tissue; lipid accumulation; obesity
    DOI:  https://doi.org/10.1155/2024/5511454
  7. Immunol Rev. 2024 May 11.
    Transcriptional and hormonal control of adipose Treg heterogeneity and function.
    Axel Kallies, Ajithkumar Vasanthakumar.
      Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation. Regulatory T cells (Tregs) that reside in the VAT suppress inflammation and protect from metabolic disease. The cellular components of VAT and its secretory products play a vital role in fostering the differentiation and maintenance of VAT Tregs. Critically, the physiology and inflammatory tone of VAT exhibit sex-specific disparities, resulting in substantial VAT Treg heterogeneity. Indeed, cytokines and sex hormones promote the differentiation of distinct populations of mature VAT Tregs, each characterized by unique phenotypes, homeostatic requirements, and functions. This review focuses on key findings that have significantly advanced our understanding of VAT Treg biology and the current state of the field, while also discussing open questions that require further exploration.
    Keywords:  Treg cells; VAT; cytokines; glucose metabolism; inflammation; sex hormones; transcriptional control
    DOI:  https://doi.org/10.1111/imr.13340
  8. Sci Adv. 2024 May 17. 10(20): eadn2867
    Serine synthesis controls mitochondrial biogenesis in macrophages.
    Chuanlong Wang, Muyang Zhao, Peng Bin, Yuyi Ye, Qingyi Chen, Zhiru Tang, Wenkai Ren.
      Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.
    DOI:  https://doi.org/10.1126/sciadv.adn2867
  9. bioRxiv. 2024 May 02. pii: 2024.05.01.592097. [Epub ahead of print]
    Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.
    Yuhan Qiu, Andrew Chen, Rebecca Yu, Pablo Llevenes, Michael Seen, Naomi Y Ko, Stefano Monti, Gerald V Denis.
      Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis.Significance: IR adipocyte exosomes modify TME, increase EMT and promote metastasis to distant organs, likely through miRNA pathways. We suggest metabolic diseases such as T2D reshape the TME, promoting metastasis and decreasing survival. Therefore, TNBC patients with T2D should be closely monitored for metastasis, with metabolic medications considered.
    DOI:  https://doi.org/10.1101/2024.05.01.592097
  10. J Mol Med (Berl). 2024 May 17.
    Mitochondria targeted esculetin administration improves insulin resistance and hyperglycemia-induced atherosclerosis in db/db mice.
    Gajalakshmi Singuru, Sriravali Pulipaka, Altab Shaikh, Shashikanta Sahoo, Aruna Jangam, Rajamannar Thennati, Srigiridhar Kotamraju.
      The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose-response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis. KEY MESSAGES: Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis. Mito-Esc improves hyperglycemia (HG)-associated insulin resistance. Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta. Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence.
    Keywords:  AMPK; Atherosclerosis; Diabetes; Insulin resistance; SIRT-1; Senescence
    DOI:  https://doi.org/10.1007/s00109-024-02449-1
  11. Nat Rev Endocrinol. 2024 May 14.
    The role of brown adipose tissue in metabolic health.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-024-00999-5
  12. J Clin Invest. 2024 May 15. pii: e173278. [Epub ahead of print]134(10):
    LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.
    Jingzhong Ding, Anh Tram Nguyen, Kurt Lohman, Michael T Hensley, Daniel Parker, Li Hou, Jackson Taylor, Deepak Voora, Janet K Sawyer, Elena Boudyguina, Michael P Bancks, Alain Bertoni, James S Pankow, Jerome I Rotter, Mark O Goodarzi, Russell P Tracy, David M Murdoch, Stephen S Rich, Bruce M Psaty, David Siscovick, Christopher Newgard, David Herrington, Ina Hoeschele, Steven Shea, James H Stein, Manesh Patel, Wendy Post, David Jacobs, John S Parks, Yongmei Liu.
      BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.
    Keywords:  Cholesterol; Diabetes; Expression profiling; Metabolism
    DOI:  https://doi.org/10.1172/JCI173278
  13. Nat Rev Endocrinol. 2024 May 17.
    AMPK as a mediator of tissue preservation: time for a shift in dogma?
    Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.
      Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.
    DOI:  https://doi.org/10.1038/s41574-024-00992-y
  14. J Nutr. 2024 May 10. pii: S0022-3166(24)00280-3. [Epub ahead of print]
    Impact of Plant-Based Dietary Fibers on Metabolic Homeostasis in High-Fat Diet Mice via Alterations in the Gut Microbiota and Metabolites.
    Elizabeth J Howard, Rachel K Meyer, Savanna N Weninger, Taylor Martinez, Hallie Wachsmuth, Marc Pignitter, Arturo Auñon-Lopez, Archana Kangath, Kalina Duszka, Haiwei Gu, Gabriele Schiro, Daniel Laubtiz, Frank A Duca.
      BACKGROUND: The gut microbiota contributes to metabolic disease, and diet shapes the gut microbiota, emphasizing the need to better understand how diet impacts metabolic disease via gut microbiota alterations. Fiber intake is linked with improvements in metabolic homeostasis in rodents and humans, which is associated with changes in the gut microbiota. However, dietary fiber is extremely heterogenous, and it is imperative to comprehensively analyze the impact of various plant-based fibers on metabolic homeostasis in an identical setting and compare the impact of alterations in the gut microbiota and bacterially derived metabolites from different fiber sources.OBJECTIVE: The objective of this study is to analyze the impact of different plant-based fibers (pectin, beta-glucan, wheat dextrin, resistant starch, and cellulose as a control) on metabolic homeostasis through alterations in the gut microbiota and its metabolites in high-fat diet (HFD)-fed mice.
    METHODS: HFD-fed mice were supplemented with 5 different fiber types (pectin, beta-glucan, wheat dextrin, resistant starch, or cellulose as a control) at 10% (w/w) for 18 weeks (n=12/group), measuring body weight, adiposity, indirect calorimetry, glucose tolerance, and the gut microbiota and metabolites.
    RESULTS: Only beta-glucan supplementation during HFD-feeding decreased adiposity and body weight gain and improved glucose tolerance compared to HFD-cellulose, while all other fibers had no effect. This was associated with increased energy expenditure and locomotor activity in mice compared to HFD-cellulose. All fibers supplemented into a HFD uniquely shifted the intestinal microbiota and cecal short-chain fatty acids, however only beta-glucan supplementation increased cecal butyrate levels. Lastly, all fibers altered the small intestinal microbiota and portal bile acid composition.
    CONCLUSIONS: These findings demonstrate that beta-glucan consumption is a promising dietary strategy for metabolic disease, possibly via increased energy expenditure through alterations in the gut microbiota and bacterial metabolites in mice.
    Keywords:  dietary fiber; gut microbiota; metabolic homeostasis; metabolites; obesity
    DOI:  https://doi.org/10.1016/j.tjnut.2024.05.003
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