Defective brown adipose tissue thermogenesis and impaired glucose metabolism in mice lacking Letmd1

Choi, Kyung Il; Kim, Jung Hak; Kong, Xiangmudong; Isik, Meltem; Zhang, Jin; Lim, Hee‐Woong; Yoon, John C.

doi:10.1016/j.celrep.2021.110104

Cited by 10 publications

(9 citation statements)

References 71 publications

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“…During the process of revising our manuscript, we came across several recently published reports that have also investigated the role of LETMD1 in BAT function 46 – 49 . While these studies consistently demonstrated the upregulation of LETMD1 in response to cold stimulation and impaired thermogenic function in Letmd1 KO mice, each report describes distinct aspects of LETMD1 function.…”

Section: Discussionmentioning

confidence: 99%

“…While these studies consistently demonstrated the upregulation of LETMD1 in response to cold stimulation and impaired thermogenic function in Letmd1 KO mice, each report describes distinct aspects of LETMD1 function. For instance, Choi et al 46 demonstrated an interaction between LETMD1 and Brg1 in the nucleus, suggesting a potential link to transcriptional regulation of BAT thermogenesis. Snyder et al 47 demonstrated that LETMD1 is essential for BAT structure and OXPHOS expression, even under thermoneutral conditions.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

et al. 2023

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Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (UCP1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport chain to generate heat. However, other mitochondrial factors required for brown adipocyte respiration and thermogenesis under cold stress are largely unknown. Here, we show LETM1 domain-containing protein 1 (LETMD1) is a BAT-enriched and cold-induced protein required for cold-stimulated respiration and thermogenesis of BAT. Proximity labeling studies reveal that LETMD1 is a mitochondrial matrix protein. Letmd1 knockout male mice display aberrant BAT mitochondria and fail to carry out adaptive thermogenesis under cold stress. Letmd1 knockout BAT is deficient in oxidative phosphorylation (OXPHOS) complex proteins and has impaired mitochondrial respiration. In addition, BAT-specific Letmd1 deficient mice exhibit phenotypes identical to those observed in Letmd1 knockout mice. Collectively, we demonstrate that the BAT-enriched mitochondrial matrix protein LETMD1 plays a tissue-autonomous role that is essential for BAT mitochondrial function and thermogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

et al. 2023

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“…LETMD1 had also the largest rank at TFCP2 locus. This gene plays a role in thermogenesis of brown adipose tissue, and mice lacking this gene were susceptible to diet-induced adiposity and impaired glucose disposal 33 .…”

Section: Pnplamentioning

confidence: 99%

Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease

Romeo,

Jamialahmadi,

De Vincentis

et al. 2024

Preprint

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Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci, we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.

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“…Ebf2 deficiency causes BAT developmental abnormalities although this is eventually compensated for in adult mice [ 128 ]. Recently, loss of the mitochondrial protein Letm1 domain containing 1 (Letmd1) was shown to produce severe abnormalities in BAT mitochondria and the expression of thermogenesis related genes, including UCP1, and caused the knockout mice to die from hypothermia upon cold exposure, resembling the UCP1 null mice [ 129 , 130 ]. β3-Adrenoreceptor-stimulated increases in energy expenditure are completely abolished in these mice.…”

Section: Thermogenic Adipose Tissue and Systemic Metabolismmentioning

confidence: 99%

Adipose Tissue and Metabolic Health

Cho

Yoon

2023

Diabetes Metab J

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In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health and highlight some recent developments in understanding and exploiting adipocyte biology. Adipose tissue plays critical roles in the regulation of systemic glucose and lipid metabolism and secretes bioactive molecules possessing endocrine, paracrine, and autocrine functions. Dysfunctional adipose tissue has a detrimental impact on metabolic health and is intimately involved in key aspects of metabolic diseases such as insulin resistance, lipid overload, inflammation, and organelle stress. Differences in the distribution of fat depots and adipose characteristics relate to divergent degrees of metabolic dysfunction found in metabolically healthy and unhealthy obese individuals. Thermogenic adipocytes increase energy expenditure via mitochondrial uncoupling or adenosine triphosphate-consuming futile substrate cycles, while functioning as a metabolic sink and participating in crosstalk with other metabolic organs. Manipulation of adipose tissue provides a wealth of opportunities to intervene and combat the progression of associated metabolic diseases. We discuss current treatment modalities for obesity including incretin hormone analogs and touch upon emerging strategies with therapeutic potential including exosome-based therapy, pharmacological activation of brown and beige adipocyte thermogenesis, and administration or inhibition of adipocyte-derived factors.

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Defective brown adipose tissue thermogenesis and impaired glucose metabolism in mice lacking Letmd1

Cited by 10 publications

References 71 publications

Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease

Adipose Tissue and Metabolic Health

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