LETM-domain containing 1 (LETMD1) protects against obesity via enhancing UCP1-independent energy expenditure in human beige adipocytes

Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1914 - 1929

Published: Jan. 2, 2025

Rationale: Brown and beige adipocytes are specialized fat cells that dissipate energy in the form of heat, hold therapeutic potential for obesity metabolic diseases. Although classical viewpoint brown solely via uncoupling protein 1 (UCP1), emerging evidence suggests importance non-canonical UCP1-independent expenditure regulating expenditure, especially human adipocytes. Leucine zipper-, EF-hand-containing transmembrane domain containing (LETMD1) was recently identified as a key maintaining UCP1 expression thermogenic activity animal models. But exact function LETMD1 its mechanism action unclear. Methods: We tested induced pluripotent stem cell (hiPSC)-derived vitro both wildtype (WT) knockout (KO) background. Furthermore, harboring doxycycline-inducible cassette were transplanted to NOD/SCID mice evaluated vivo setting. RNA-Seq conducted normal LETMD1-overexpressing examine genes pathways regulated by LETMD1. Using knock-in iPSC line, preclinical small molecule compound library screened compounds increasing The effects inducing examined Results: plays an essential role engaging dissipation, manner independent UCP1, Transplantation improved whole-body metabolism recipient UCP1. Mechanistically enhances transcription PPARGC1A, regulator mitochondrial biogenesis. related including creatine futile cycle, also stimulated upon overexpression. reporter adipocytes, SP-8356 significantly expression. Oral administration counteracted body weight gain disorders mice. Conclusion: Increased action, either genetically or pharmacologically,

Language: Английский

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The autophagy receptor Ncoa4 controls PPARγ activity and thermogenesis in brown adipose tissue

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Abstract Adipose tissue dysfunction leads to a variety of deleterious systemic consequences including ectopic lipid deposition and impaired insulin sensitivity. PPARγ is major regulator adipocyte differentiation functionality thus determinant metabolic health. We recently reported that deletion fatty acid synthase (AdFasnKO) impairs autophagy in association with striking upregulation genes controlled by PPARγ, thermogenic uncoupling protein 1 (Ucp1). In this present study, screening for coactivators regulated revealed denoted as Nuclear receptor coactivator 4 (Ncoa4), known mediate ferritinophagy interact other nuclear receptors. Indeed, we found Ncoa4 upregulated the early phase required adipogenesis. also elevated FasnKO adipocytes necessary full Ucp1 expression vitro , even response norepinephrine. Consistent these findings, adipose-selective knockout (AdNcoa4KO mice) brown adipose cold-induced thermogenesis. Adipose-selective double KO Fasn plus (AdFasnNcoa4DKO prevents classic target normally observed white AdFasnKO mice, but not expression. These findings reveal novel activity biology suggest manipulation flux modulates key functions via actions.

Language: Английский

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Irisin reverses high-fat diet-induced metabolic dysfunction via activation of brown adipose tissue in mice

International Journal of Obesity, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Language: Английский

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Regulation of UCP1 expression by PPARα and pemafibrate in human beige adipocytes

Life Sciences, Journal Year: 2025, Volume and Issue: 363, P. 123406 - 123406

Published: Jan. 17, 2025

Language: Английский

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Single-nucleus RNA sequencing reveals dynamic changes in the microenvironment of visceral adipose tissue and metabolic characteristics after cold exposure

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 16

Published: March 24, 2025

Introduction Visceral adipose tissue (VAT) plays a crucial role in regulating systemic metabolic balance. Excess accumulation of VAT is closely associated with various disorders, process that involves the coordinated actions multiple cell types within tissue. Cold exposure, as potential intervention, has been proposed to improve dysfunction. However, heterogeneity and its comprehensive characteristics under cold exposure remain unclear. Methods We collected epididymal white (eWAT) C57BL/6J mice after at three different time points for single-nucleus RNA sequencing (snRNA-seq) analysis. Results successfully identified ten major eWAT, enabling understanding dynamic changes eWAT microenvironment features during exposure. This study revealed 1 day reduced cellular activity intercellular communication including receptor-ligand-based metabolite-mediated interactions. 14 days acclimation, adipocytes was significantly enhanced, restored. Additionally, prolonged promoted formation distinct adipocyte subpopulation may be UCP1-independent thermogenesis. These new homeostatic state established by adapt environment. The also importance adipocytes, stem progenitor cells, myeloid endothelial cells adaptation. Discussion research provides valuable insights into heterogeneity, remodeling, reprogramming It highlights critical transcriptional dynamics perspectives on prevention treatment diseases.

Language: Английский

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The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 4, 2025

Abstract Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by kinase b (CKB) and phosphocreatine hydrolysis tissue-nonspecific alkaline phosphatase (TNAP), key thermogenic mechanism BAT. Reintroducing mitochondrial-targeted CKB into interscapular adipocytes vivo restores cold tolerance mice lacking native UCP1 CKB, TNAP-dependent manner. Furthermore, with adipocyte-specific co-deletion TNAP exhibit severe cold-intolerance. These findings challenge view that depends solely because insufficient synthase activity establishes FCC physiologically relevant

Language: Английский

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Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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The complexity of adipocyte heterogeneity

Nature Reviews Endocrinology, Journal Year: 2024, Volume and Issue: 20(10), P. 569 - 569

Published: Aug. 27, 2024

Language: Английский

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Targeting Dlat-Trpv3 pathway by hyperforin elicits non-canonical promotion of adipose thermogenesis as an effective anti-obesity strategy

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

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