bims-obesme 2024-10-06 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒10‒06
eight papers selected by
Xiong Weng, University of Edinburgh

Sirtuin 3 reinforces acylcarnitine metabolism and maintains thermogenesis in brown adipose tissue of aging mice.
Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.
Ciliary localization of GPR75 promotes fat accumulation in mice.
LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism.
Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism.
Lipid Droplets Big and Small: Basic Mechanisms That Make Them All.
A novel long non-coding RNA connects obesity to impaired adipocyte function.
Epigenetic Regulation is involved in Reversal of Obesity.

Aging Cell. 2024 Sep 30. e14332

Sirtuin 3 reinforces acylcarnitine metabolism and maintains thermogenesis in brown adipose tissue of aging mice.

Kuiliang Zhang, Yucheng Wang, Yujie Sun, Lamei Xue, Yu Wang, Chenzhipeng Nie, Mingcong Fan, Haifeng Qian, Hao Ying, Li Wang, Yan Li.

  Acylcarnitine (ACar) is a novel fuel source for activating thermogenesis in brown adipose tissue (BAT). However, whether ACar metabolism underlies BAT thermogenesis decline with aging remain unclear. Here, the L-carnitine-treated young and aging mice were used to investigate the effects of activation of ACar metabolism on BAT thermogenesis during aging. We showed that long term L-carnitine feeding, which results in an elevation in circulating ACar levels, failed to improve cold sensitivity of aging mice, which still displayed impaired thermogenesis and ACar metabolism in interscapular BAT (iBAT). The RNA-sequencing was used to identify the key regulator for the response of aging mice to LCar induced activation of ACar metabolism in BAT, and we identified Sirt3 as a key regulator for the response of aging mice to L-carnitine induced activation of ACar metabolism in iBAT. Then the adipose-specific Sirt3 knockout (Sirt3 AKO) mice were used to investigate the role of Sirt3 in ACar metabolism and thermogenesis of BAT and explore the underlying mechanism, and the results showed that Sirt3 AKO mice displayed defective ACar metabolism and thermogenesis in iBAT. Mechanically, Sirt3 regulated ACar metabolism via HIF1α-PPARα signaling pathway to promote iBAT thermogenesis, and knockdown or inhibition of HIF1α ameliorated impaired ACar metabolism and thermogenesis of iBAT in the absence of Sirt3. Collectively, we propose that Sirt3 regulated ACar metabolism is critical in maintaining thermogenesis in BAT of aging mice, which can promote the development of anti-aging intervention strategy.

Keywords:  Sirt3; acylcarnitine metabolism; aging; brown adipose tissue; thermogenesis

DOI:  https://doi.org/10.1111/acel.14332
Nat Commun. 2024 Oct 02. 15(1): 8533

Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.

Sanil Patel, Khatanzul Ganbold, Chung Hwan Cho, Juwairriyyah Siddiqui, Ramazan Yildiz, Njeri Sparman, Shani Sadeh, Christy M Nguyen, Jiexin Wang, Julian P Whitelegge, Susan K Fried, Hironori Waki, Claudio J Villanueva, Marcus M Seldin, Shinya Sakaguchi, Wilfried Ellmeier, Peter Tontonoz, Prashant Rajbhandari.

White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.

DOI: https://doi.org/10.1038/s41467-024-52917-y
J Clin Invest. 2024 Oct 01. pii: e185059. [Epub ahead of print]134(19):

Ciliary localization of GPR75 promotes fat accumulation in mice.

Marcelo Chávez, Anushweta Asthana, Peter K Jackson.

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands.

DOI: https://doi.org/10.1172/JCI185059
Hepatology. 2024 Aug 29.

LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism.

Zhihong Yang, Yanchao Jiang, Jing Ma, Li Wang, Sen Han, Nazmul Huda, Praveen Kusumanchi, Hui Gao, Themis Thoudam, Zhaoli Sun, Suthat Liangpunsakul.

BACKGROUND AND AIMS: Long noncoding RNAs constitute a significant portion of the human genome. Among these, lncRNA H19, initially identified for its high expression during fetal development followed by a decline in the liver postnatally, re-emerges in various liver diseases. However, its specific role in alcohol-associated liver disease (ALD) remains unclear.APPROACH AND RESULTS: Elevated H19 levels were detected in peripheral blood and livers of patients with alcohol-associated cirrhosis and hepatitis, as well as in livers of ethanol-fed mice. Hepatic overexpression of H19 exacerbated ethanol-induced liver steatosis and injury. Metabolomics analysis revealed decreased methionine levels in H19-overexpressed mouse livers, attributable to H19-mediated inhibition of betaine homocysteine methyltransferase (BHMT), a crucial enzyme in methionine synthesis. H19 regulated BHMT alternative splicing through polypyrimidine tract-binding protein 1 (PTBP1), resulting in a reduced Bhmt protein-coding variant. The maternally specific knockout of H19 (H19Mat+/-) or liver-specific knockout of the H19 differentially methylated domain (H19DMDHep-/-) in ethanol-fed mice upregulated BHMT expression and ameliorated hepatic steatosis. Furthermore, BHMT restoration counteracted H19-induced ethanol-mediated hepatic steatosis.
CONCLUSIONS: This study identifies a novel mechanism whereby H19, via PTBP1-mediated BHMT regulation, influences methionine metabolism in ALD. Targeting the H19-PTBP1-BHMT pathway may offer new therapeutic avenues for ALD.

DOI: https://doi.org/10.1097/HEP.0000000000001078
Gut. 2024 Oct 02. pii: gutjnl-2024-332602. [Epub ahead of print]

Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism.

Anna Castells-Nobau, José Maria Moreno-Navarrete, Lisset de la Vega-Correa, Irene Puig, Massimo Federici, Jiuwen Sun, Remy Burcelin, Laurence Guzylack-Piriou, Pierre Gourdy, Laurent Cazals, María Arnoriaga-Rodríguez, Gema Frühbeck, Luisa Maria Seoane, José López-Miranda, Francisco J Tinahones, Carlos Dieguez, Marc-Emmanuel Dumas, Vicente Pérez-Brocal, Andrés Moya, Nikolaos Perakakis, Geltrude Mingrone, Stefan Bornstein, Jose Ignacio Rodriguez Hermosa, Ernesto Castro, Jose Manuel Fernández-Real, Jordi Mayneris-Perxachs.

  BACKGROUND: The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity.OBJECTIVE: To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues.
DESIGN: Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose).
RESULTS: Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in Drosophila melanogaster validated these human insulin sensitivity-associated changes.
CONCLUSION: These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now.

Keywords:  INTESTINAL BACTERIA; LIVER; OBESITY

DOI:  https://doi.org/10.1136/gutjnl-2024-332602
Annu Rev Cell Dev Biol. 2024 Oct;40(1): 143-168

Lipid Droplets Big and Small: Basic Mechanisms That Make Them All.

Robin W Klemm, Pedro Carvalho.

  Lipid droplets (LDs) are dynamic storage organelles with central roles in lipid and energy metabolism. They consist of a core of neutral lipids, such as triacylglycerol, which is surrounded by a monolayer of phospholipids and specialized surface proteins. The surface composition determines many of the LD properties, such as size, subcellular distribution, and interaction with partner organelles. Considering the diverse energetic and metabolic demands of various cell types, it is not surprising that LDs are highly heterogeneous within and between cell types. Despite their diversity, all LDs share a common biogenesis mechanism. However, adipocytes have evolved specific adaptations of these basic mechanisms, enabling the regulation of lipid and energy metabolism at both the cellular and organismal levels. Here, we discuss recent advances in the understanding of both the general mechanisms of LD biogenesis and the adipocyte-specific adaptations controlling these fascinating organelles.

Keywords:  LD; LD biogenesis; LD contact sites; LD heterogeneity; LD protein targeting; LD size control; adipocyte; lipid droplet

DOI:  https://doi.org/10.1146/annurev-cellbio-012624-031419
Mol Metab. 2024 Oct 01. pii: S2212-8778(24)00171-6. [Epub ahead of print] 102040

A novel long non-coding RNA connects obesity to impaired adipocyte function.

Aina Lluch, Jèssica Latorre, Núria Oliveras-Cañellas, Ana Fernández-Sánchez, José M Moreno-Navarrete, Anna Castells-Nobau, Ferran Comas, Maria Buxò, José I Rodríguez-Hermosa, María Ballester, Isabel Espadas, Alejandro Martin-Montalvo, Birong Zhang, You Zhou, Ralph Burkhardt, Marcus Höring, Gerhard Liebisch, Ainara Castellanos-Rubio, Izortze Santin, Asha Kar, Markku Laakso, Päivi Pajukanta, Vesa M Olkkonen, José M Fernández-Real, Francisco J Ortega.

  BACKGROUND: Long non-coding RNAs (lncRNAs) can perform tasks of key relevance in fat cells, contributing, when defective, to the burden of obesity and its sequelae. Here, scrutiny of adipose tissue transcriptomes before and after bariatric surgery (GSE53378) granted identification of 496 lncRNAs linked to the obese phenotype. Only expression of linc-GALNTL6-4 displayed an average recovery over 2-fold and FDR-adjusted p-value <0.0001 after weight loss. The aim of the present study was to investigate the impact on adipocyte function and potential clinical value of impaired adipose linc-GALNTL6-4 in obese subjects.METHODS: We employed transcriptomic analysis of public dataset GSE199063, and cross validations in two large transversal cohorts to report evidence of a previously unknown association of adipose linc-GALNTL6-4 with obesity. We then performed functional analyses in human adipocyte cultures, genome-wide transcriptomics, and untargeted lipidomics in cell models of loss and gain of function to explore the molecular implications of its associations with obesity and weight loss.
RESULTS: The expression of linc-GALNTL6-4 in human adipose tissue is adipocyte-specific and co-segregates with obesity, being normalized upon weight loss. This co-segregation is demonstrated in two longitudinal weight loss studies and two cross-sectional samples. While compromised expression of linc-GALNTL6-4 in obese subjects is primarily due to the inflammatory component in the context of obesity, adipogenesis requires the transcriptional upregulation of linc-GALNTL6-4, the expression of which reaches an apex in terminally differentiated adipocytes. Functionally, we demonstrated that the knockdown of linc-GALNTL6-4 impairs adipogenesis, induces alterations in the lipidome, and leads to the downregulation of genes related to cell cycle, while propelling in adipocytes inflammation, impaired fatty acid metabolism, and altered gene expression patterns, including that of apolipoprotein C1 (APOC1). Conversely, the genetic gain of linc-GALNTL6-4 ameliorated differentiation and adipocyte phenotype, putatively by constraining APOC1, also contributing to the metabolism of triglycerides in adipose.
CONCLUSIONS: Current data unveil the unforeseen connection of adipocyte-specific linc-GALNTL6-4 as a modulator of lipid homeostasis challenged by excessive body weight and meta-inflammation.

Keywords:  adipocytes; adipose tissue; linc-GALNTL6-4; obesity; triglycerides

DOI:  https://doi.org/10.1016/j.molmet.2024.102040
Neurosci Biobehav Rev. 2024 Sep 27. pii: S0149-7634(24)00375-0. [Epub ahead of print] 105906

Epigenetic Regulation is involved in Reversal of Obesity.

Kayla Rapps, Aron Weller, Noam Meiri.

  Epigenetic processes play a crucial role in mediating the impact of environmental energetic challenges, from overconsumption to starvation. Over-nutrition of energy-dense foods and sedentary lifestyles contribute to the development of obesity, characterized by excessive fat storage and impaired metabolic signaling, stemming from disrupted brain signaling. Conversely, dieting and physical activity facilitate body weight rebalancing and trigger adaptive neural responses. These adaptations involve the upregulation of neurogenesis, synaptic plasticity and optimized brain function and energy homeostasis, balanced hormone signaling, normal metabolism, and reduced inflammation. The transition of the brain from a maladaptive to an adaptive state is partially guided by epigenetic mechanisms. While epigenetic mechanisms underlying obesity-related brain changes have been described, their role in mediating the reversal of maladaptation/obesity through lifestyle interventions remains less explored. This review focuses on elucidating epigenetic mechanisms involved in hypothalamic adaptations induced by lifestyle interventions. Given that lifestyle interventions are widely prescribed and accessible approaches for weight loss and maintenance, it is our challenge to uncover epigenetic mechanisms moderating these hypothalamic-functional beneficial changes.

Keywords:  caloric restriction; dieting; epigenetics; exercise; hypothalamus; obesity

DOI:  https://doi.org/10.1016/j.neubiorev.2024.105906