TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

Choi, Cheoljun; Son, Yeonho; Kim, Jin‐Young; Cho, Yoon Keun; Saha, Abhirup; Kim, Minsu; Im, Hyeonyeong; Kim, Kyungmin; Han, Jeong‐Won; Lee, Sang Eun; Seong, Je Kyung; Lee, Yun-Hee

doi:10.2337/db21-0145

Cited by 13 publications

(8 citation statements)

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“…Furthermore, primary hepatocytes from WT but not KO mice at 3‐month‐old age expressed Tm4sf5 mRNA. However, BAT from WT and KO mice did not express Tm4sf5 mRNA, as reported previously (Choi et al., 2021; Kim et al., 2021) (Figure 1I).…”

Section: Resultssupporting

confidence: 87%

Liver‐originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance

Jung

Kim

et al. 2022

J of Extracellular Vesicle

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Transmembrane 4 L six family member 5 (TM4SF5) is involved in chronic liver disease, although its role in glucose homeostasis remains unknown. TM4SF5 deficiency caused age-dependent glucose (in)tolerance with no link to insulin sensitivity. Further, hepatic TM4SF5 binding to GLUT1 promoted glucose uptake and glycolysis. Excessive glucose repletion caused hepatocytes to secrete small extracellular vesicles (sEVs) loaded with TM4SF5 (hep-sEV Tm4sf5 ), suggesting a role for sEV Tm4sf5 in glucose metabolism and homeostasis. Hep-sEV Tm4sf5 were smaller than sEV Control and recruit proteins for efficient organ tropism. Liver-derived sEVs, via a liver-closed vein circuit (LCVC) using hepatic TM4SF5-overexpressing (Alb-Tm4sf5 TG) mice (liv-sEV Tm4sf5 ), improved glucose tolerance in Tmsf −/− KO mice and targeted brown adipose tissues (BATs), possibly allowing the clearance of blood glucose as heat independent of UCP1. Taken together, hep-sEV Tm4sf5 might clear high extracellular glucose levels more efficiently by targeting BAT compared with hep-sEV Control , suggesting an insulin-like role for sEV™ 4SF5 in affecting age-related metabolic status and thus body weight (BW).

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Section: Resultssupporting

confidence: 87%

Liver‐originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance

Jung

Kim

et al. 2022

J of Extracellular Vesicle

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“…Autophagy is involved in the regulation of lipid metabolism, and its dysregulation in adipose tissue is associated with the development of metabolic diseases ( 70 , 71 ). Dysregulation of autophagy alters energy metabolism in hypothalamic neurons and white adipose tissue (WAT).…”

Section: Discussionmentioning

confidence: 99%

High-fiber-diet-related metabolites improve neurodegenerative symptoms in patients with obesity with diabetes mellitus by modulating the hippocampal–hypothalamic endocrine axis

et al. 2023

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ObjectiveThrough transcriptomic and metabolomic analyses, this study examined the role of high-fiber diet in obesity complicated by diabetes and neurodegenerative symptoms.MethodThe expression matrix of high-fiber-diet-related metabolites, blood methylation profile associated with pre-symptomatic dementia in elderly patients with type 2 diabetes mellitus (T2DM), and high-throughput single-cell sequencing data of hippocampal samples from patients with Alzheimer's disease (AD) were retrieved from the Gene Expression Omnibus (GEO) database and through a literature search. Data were analyzed using principal component analysis (PCA) after quality control and data filtering to identify different cell clusters and candidate markers. A protein–protein interaction network was mapped using the STRING database. To further investigate the interaction among high-fiber-diet-related metabolites, methylation-related DEGs related to T2DM, and single-cell marker genes related to AD, AutoDock was used for semi-flexible molecular docking.ResultBased on GEO database data and previous studies, 24 marker genes associated with high-fiber diet, T2DM, and AD were identified. Top 10 core genes include SYNE1, ANK2, SPEG, PDZD2, KALRN, PTPRM, PTPRK, BIN1, DOCK9, and NPNT, and their functions are primarily related to autophagy. According to molecular docking analysis, acetamidobenzoic acid, the most substantially altered metabolic marker associated with a high-fiber diet, had the strongest binding affinity for SPEG.ConclusionBy targeting the SPEG protein in the hippocampus, acetamidobenzoic acid, a metabolite associated with high-fiber diet, may improve diabetic and neurodegenerative diseases in obese people.

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“…Glycerol and free fatty acid (FFA) levels in media were measured using glycerol reagent (Sigma-Aldrich, F6428, St. Louis, MO, USA) and NEFA reagents (WAKO, 436-91693, Osaka, Japan) following the manufacturer’s product protocol as previously described [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

“…Ex vivo electron transport activity related to mitochondrial oxidative phosphorylation was evaluated by monitoring the reduction of 0.1% triphenyltetrazolium chloride (TTC, Sigma, T8877, St. Louis, MO, USA) as described previously [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Anti-obesity effects of the dual-active adenosine A2A/A3 receptor-ligand LJ-4378

Kim

Son

et al. 2022

Int J Obes

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Background and objectives A2A adenosine receptor (A2AAR)-mediated signaling in adipose tissues has been investigated as a potential target for obesity-related metabolic diseases. LJ-4378 has been developed as a dual-acting ligand with A2AAR agonist and A3 adenosine receptor (A3AR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms. Methods Immortalized brown adipocytes were used for in vitro analysis. A high-fat diet (HFD)-induced obesity and cell death-inducing DFFA-like effector A reporter mouse models were used for in vivo experiments. The effects of LJ-4378 on lipolysis and mitochondrial metabolism were evaluated using immunoblotting, mitochondrial staining, and oxygen consumption rate analyses. The in vivo anti-obesity effects of LJ-4378 were evaluated using indirect calorimetry, body composition analyses, glucose tolerance tests, and histochemical analyses. Results In vitro LJ-4378 treatment increased the levels of brown adipocyte markers and mitochondrial proteins, including uncoupling protein 1. The effects of LJ-4378 on lipolysis of adipocytes were more potent than those of the A2AAR agonist or A3AR antagonist. In vivo, LJ-4378 treatment increased energy expenditure by 17.0% (P value < 0.0001) compared to vehicle controls. LJ-4378 (1 mg/kg, i.p.) treatment for 10 days reduced body weight and fat content by 8.24% (P value < 0.0001) and 24.2% (P value = 0.0044), respectively, and improved glucose tolerance in the HFD-fed mice. LJ-4378 increased the expression levels of brown adipocyte markers and mitochondrial proteins in interscapular brown and inguinal white adipose tissue. Conclusion These findings support the in vivo anti-obesity effects of LJ-4378, and suggest a novel therapeutic approach to combat obesity and related metabolic diseases.

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TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

Cited by 13 publications

References 50 publications

Liver‐originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance

Liver‐originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance

High-fiber-diet-related metabolites improve neurodegenerative symptoms in patients with obesity with diabetes mellitus by modulating the hippocampal–hypothalamic endocrine axis

Anti-obesity effects of the dual-active adenosine A2A/A3 receptor-ligand LJ-4378

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