bims-obesme 2024-05-12 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒05‒12
eleven papers selected by
Xiong Weng, University of Edinburgh

Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice.
Adipsin and Adipocyte-derived C3aR1 Regulate Thermogenic Fat in a Sex-dependent Fashion.
AGPAT3 Deficiency Impairs Adipocyte Differentiation and Leads to a Lean Phenotype in Mice.
Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease.
Adipose Tissue Dynamics, Thermogenesis, and Interorgan Connections for Preventing Obesity and Metabolic Disorders.
Neuroanatomical dissection of the MC3R circuitry regulating energy rheostasis.
The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis.
miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling.
Intermittent fasting influences immunity and metabolism.
Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation.
Nature of epigenetic aging from a single-cell perspective.

Front Mol Biosci. 2024 ;11 1397565

Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice.

Lucia Cilenti, Jacopo Di Gregorio, Rohit Mahar, Fei Liu, Camilla T Ambivero, Muthu Periasamy, Matthew E Merritt, Antonis S Zervos.

  Obesity is a growing epidemic affecting millions of people worldwide and a major risk factor for a multitude of chronic diseases and premature mortality. Accumulating evidence suggests that mitochondria have a profound role in diet-induced obesity and the associated metabolic changes, but the molecular mechanisms linking mitochondria to obesity remain poorly understood. Our studies have identified a new function for mitochondrial MUL1 E3 ubiquitin ligase, a protein known to regulate mitochondrial dynamics and mitophagy, in the control of energy metabolism and lipogenesis. Genetic deletion of Mul1 in mice impedes mitophagy and presents a metabolic phenotype that is resistant to high-fat diet (HFD)-induced obesity and metabolic syndrome. Several metabolic and lipidomic pathways are perturbed in the liver and white adipose tissue (WAT) of Mul1(-/-) animals on HFD, including the one driven by Stearoyl-CoA Desaturase 1 (SCD1), a pivotal regulator of lipid metabolism and obesity. In addition, key enzymes crucial for lipogenesis and fatty acid oxidation such as ACC1, FASN, AMPK, and CPT1 are also modulated in the absence of MUL1. The concerted action of these enzymes, in the absence of MUL1, results in diminished fat storage and heightened fatty acid oxidation. Our findings underscore the significance of MUL1-mediated mitophagy in regulating lipogenesis and adiposity, particularly in the context of HFD. Consequently, our data advocate the potential of MUL1 as a therapeutic target for drug development in the treatment of obesity, insulin resistance, NAFLD, and cardiometabolic diseases.

Keywords:  MUL1; SCD1; lipogenesis; mitophagy; obesity

DOI:  https://doi.org/10.3389/fmolb.2024.1397565
JCI Insight. 2024 May 07. pii: e178925. [Epub ahead of print]

Adipsin and Adipocyte-derived C3aR1 Regulate Thermogenic Fat in a Sex-dependent Fashion.

Lunkun Ma, Ankit Gilani, Alfonso Rubio-Navarro, Eric Cortada, Ang Li, Shannon M Reilly, Liling Tang, James C Lo.

  Thermogenesis in beige/brown adipose tissues can be leveraged to combat metabolic disorders such as type 2 diabetes and obesity. The complement system plays pleiotropic roles in metabolic homeostasis and organismal energy balance with canonical effects on immune cells and non-canonical effects on non-immune cells. The adipsin/C3a/C3aR1 pathway stimulates insulin secretion and sustains pancreatic beta cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that male Adipsin/Cfd knockout mice exhibit increased energy expenditure and white adipose tissue (WAT) browning. In addition, male adipocyte-specific C3aR1 knockout mice exhibit enhanced WAT thermogenesis and increased respiration. In stark contrast, female adipocyte-specific C3aR1 knockout mice display decreased brown fat thermogenesis and are cold intolerant. Female mice express lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 is also lower in female subcutaneous adipose tissue than males. Collectively, these results reveal sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis and defense against cold stress. Our findings establish a newly discovered role of the alternative complement pathway in adaptive thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.

Keywords:  Adipose tissue; Complement; Inflammation; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.178925
Am J Physiol Endocrinol Metab. 2024 May 08.

AGPAT3 Deficiency Impairs Adipocyte Differentiation and Leads to a Lean Phenotype in Mice.

Hongyi Zhou, Kendra Fick, Vijay Patel, Lisa Renee Hilton, Ha Won Kim, Zsolt Bagi, Neal L Weintraub, Weiqin Chen.

  Acylglycerophosphate acyltransferases (AGPATs) catalyze the de novo formation of phosphatidic acid to synthesize glycerophospholipids and triglycerides. AGPATs demonstrate unique physiological roles despite a similar biochemical function. AGPAT3 is highly expressed in the testis, kidney, and liver, with intermediate expression in adipose tissue. Loss of Agpat3 is associated with reproductive abnormalities and visual dysfunction. However, the role of AGPAT3 in adipose tissue and whole-body metabolism has not been investigated. We found that male Agpat3-KO mice exhibited reduced body weights with decreased white and brown adipose tissue mass. Such changes were less pronounced in the female Agpat3-KO mice. Agpat3-KO mice have reduced plasma insulin growth factor 1 (IGF1) and insulin levels and diminished circulating lipid metabolites. They manifested intact glucose homeostasis and insulin sensitivity despite a lean phenotype. Agpat3-KO mice maintained an energy balance with normal food intake, energy expenditure, and physical activity, except for increased water intake. Their adaptive thermogenesis was also normal despite reduced brown adipose mass and triglyceride content. Mechanistically, Agpat3 was elevated during mouse and human adipogenesis and enriched in adipocytes. Agpat3-knockdown 3T3-L1 cells and Agpat3-deficient mouse embryonic fibroblasts (MEFs) have impaired adipogenesis in vitro. Interestingly, pioglitazone treatment rescued the adipogenic deficiency in Agpat3 deficient cells. We conclude that AGPAT3 regulates adipogenesis and adipose development. It is possible that adipogenic impairment in Agpat3 deficient cells potentially leads to reduced adipose mass. Findings from this work support the unique role of AGPAT3 in adipose tissue.

Keywords:  AGPAT; Adipocyte differentiation; Energy homeostasis; Lipid metabolism

DOI:  https://doi.org/10.1152/ajpendo.00012.2024
Cell Metab. 2024 May 07. pii: S1550-4131(24)00126-8. [Epub ahead of print]36(5): 947-968

Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease.

Tao Bo, Ling Gao, Zhenyu Yao, Shanshan Shao, Xuemin Wang, Christopher G Proud, Jiajun Zhao.

  Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.

Keywords:  MASLD; extrahepatic factors; glucose metabolism; insulin resistance; lipid metabolism

DOI:  https://doi.org/10.1016/j.cmet.2024.04.006
JMA J. 2024 Apr 15. 7(2): 172-177

Adipose Tissue Dynamics, Thermogenesis, and Interorgan Connections for Preventing Obesity and Metabolic Disorders.

Masaji Sakaguchi.

  Adipose tissues, such as white, brown, and beige tissues, play pivotal roles in maintaining energy balance and metabolic health. Whereas white adipocytes store energy, brown and beige adipocytes exhibit high energy expenditure owing to their distinct mitochondrial density and UCP1 expression. Dysfunction in these tissues contributes to metabolic disorders such as type 2 diabetes and cardiovascular diseases. Adipose tissue expansion through cell enlargement or increased cell numbers caused by excess energy storage in white adipocytes substantially influences metabolic health. In obesity, hypertrophic adipocytes trigger inflammation, fibrosis, and hypoxia, whereas smaller adipocytes exert favorable metabolic effects, contributing to insulin sensitivity. Brown and beige adipocytes consume energy for thermogenesis to maintain body temperature, contributing to metabolic homeostasis. The intricate interactions between brown adipose tissues and various organs, such as the liver and heart, highlight the systemic implications of adipose tissue functions. Understanding the complex underlying mechanisms may lead to the development of innovative therapies targeting metabolic disorders by modulating the functions of brown adipose tissue and its interactions with other physiological systems. In this review, we discuss insights into the mechanisms underlying the dysregulation of metabolism owing to abnormalities in adipose tissue remodeling. We focus on the endocrine functions of thermogenic brown and beige adipocytes and explore the interorgan interactions that influence whole-body metabolism.

Keywords:  UCP1; adipokines; adipose tissue remodeling; brown adipocyte; insulin resistance; interorgan connections; thermogenesis; type 2 diabetes

DOI:  https://doi.org/10.31662/jmaj.2023-0218
bioRxiv. 2024 Apr 26. pii: 2024.04.22.590573. [Epub ahead of print]

Neuroanatomical dissection of the MC3R circuitry regulating energy rheostasis.

Ingrid Camila Possa-Paranhos, Jared Butts, Emma Pyszka, Christina Nelson, Dajin Cho, Patrick Sweeney.

Although mammals resist both acute weight loss and weight gain, the neural circuitry mediating bi-directional defense against weight change is incompletely understood. Global constitutive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioral response to both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain following anabolic challenges and increased weight loss following anorexic challenges (i.e. impaired energy rheostasis). However, the brain regions mediating this phenotype remain incompletely understood. Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase to selectively delete MC3R from medial hypothalamus (MH) in adult mice. Behavioral assays were performed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anorexic challenges. Complementary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific medial hypothalamic brain regions mediating the role of MC3R in energy homeostasis. Finally, we performed RNAscope in situ hybridization to map changes in the mRNA expression of MC3R, POMC, and AgRP following energy rheostatic challenges. Our results demonstrate that MC3R deletion in MH increased feeding and weight gain following acute high fat diet feeding in males, and enhanced the anorexic effects of semaglutide, in a sexually dimorphic manner. Additionally, activation of DMH MC3R neurons increased energy expenditure and locomotion. Together, these results demonstrate that MC3R mediated effects on energy rheostasis result from the loss of MC3R signaling in the medial hypothalamus of adult animals and suggest an important role for DMH MC3R signaling in energy rheostasis. Key Points: MC3R signaling regulates energy rheostasis in adult miceMedial hypothalamus regulates energy rheostasis in adult miceEnergy rheostasis alters mRNA levels of AgRP and MC3R in DMHDMH MC3R neurons increase locomotion and energy expenditureMC3R expression in DMH is sexually dimorphic.

DOI: https://doi.org/10.1101/2024.04.22.590573
JCI Insight. 2024 May 07. pii: e164771. [Epub ahead of print]

The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis.

Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue.

  Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4-20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces, whereas Suv420h2 overexpression significantly increases Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to down-regulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.

Keywords:  Adipose tissue; Metabolism; Obesity; Uncoupling proteins

DOI:  https://doi.org/10.1172/jci.insight.164771
Cardiovasc Res. 2024 May 04. pii: cvae102. [Epub ahead of print]

miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling.

Shruti Rawal, Vinay Randhawa, Syed Husain Mustafa Rizvi, Madhur Sachan, Akm Khyrul Wara, Daniel Pérez-Cremades, Robert M Weisbrod, Naomi M Hamburg, Mark W Feinberg.

  AIMS: Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear.METHODS AND RESULTS: MiRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells (PBMCs) from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxLDL-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation (lL-1β, TNF-a, IL-6). Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signaling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes.
CONCLUSION: These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.

Keywords:  GPR91; atherosclerosis; diabetes; macrophage; microRNA; succinate

DOI:  https://doi.org/10.1093/cvr/cvae102
Trends Endocrinol Metab. 2024 May 07. pii: S1043-2760(24)00097-3. [Epub ahead of print]

Intermittent fasting influences immunity and metabolism.

Daniel M Marko, Meghan O Conn, Jonathan D Schertzer.

  Intermittent fasting (IF) modifies cell- and tissue-specific immunometabolic responses that dictate metabolic flexibility and inflammation during obesity and type 2 diabetes (T2D). Fasting forces periods of metabolic flexibility and necessitates increased use of different substrates. IF can lower metabolic inflammation and improve glucose metabolism without lowering obesity and can influence time-dependent, compartmentalized changes in immunity. Liver, adipose tissue, skeletal muscle, and immune cells communicate to relay metabolic and immune signals during fasting. Here we review the connections between metabolic and immune cells to explain the divergent effects of IF compared with classic caloric restriction (CR) strategies. We also explore how the immunometabolism of metabolic diseases dictates certain IF outcomes, where the gut microbiota triggers changes in immunity and metabolism during fasting.

Keywords:  immunity; intermittent fasting; metabolism; obesity

DOI:  https://doi.org/10.1016/j.tem.2024.04.014
Aging Cell. 2024 May 09. e14190

Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation.

Maria Elisa Caetano-Silva, Akriti Shrestha, Audrey F Duff, Danica Kontic, Patricia C Brewster, Mikaela C Kasperek, Chia-Hao Lin, Derek A Wainwright, Diego Hernandez-Saavedra, Jeffrey A Woods, Michael T Bailey, Thomas W Buford, Jacob M Allen.

  Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin. Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.

Keywords:  TLR4; aging; antibiotics; inflammation; microbiome

DOI:  https://doi.org/10.1111/acel.14190
Nat Aging. 2024 May 09.

Nature of epigenetic aging from a single-cell perspective.

Andrei E Tarkhov, Thomas Lindstrom-Vautrin, Sirui Zhang, Kejun Ying, Mahdi Moqri, Bohan Zhang, Alexander Tyshkovskiy, Orr Levy, Vadim N Gladyshev.

Age-related changes in DNA methylation (DNAm) form the basis of the most robust predictors of age-epigenetic clocks-but a clear mechanistic understanding of exactly which aspects of aging are quantified by these clocks is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the dynamics of tissue and single-cell DNAm in mice. We compare these changes during early development with those observed during adult aging in mice, and corroborate our analyses with a single-cell RNA sequencing analysis within the same multiomics dataset. We show that epigenetic aging involves co-regulated changes as well as a major stochastic component, and this is consistent with transcriptional patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns. Together, our analyses increase our understanding of the basis of epigenetic clocks and highlight potential opportunities for targeting aging and evaluating longevity interventions.

DOI: https://doi.org/10.1038/s43587-024-00616-0