2 Genetics of Adipose-Tissue Development and Function in Humans

Obesity ◽  
2007 ◽  
pp. 436-451
2018 ◽  
Author(s):  
Younghoon Jang ◽  
Chaochen Wang ◽  
Aaron Broun ◽  
Young-Kwon Park ◽  
Lenan Zhuang ◽  
...  

AbstractHistone H3K4 mono-methyltransferases MLL3 and MLL4 (MLL3/4) are required for enhancer activation during cell differentiation, though the mechanism is incompletely understood. To address MLL3/4 enzymatic activity in enhancer regulation, we have generated two mouse lines: one expressing H3.3K4M, a lysine-4-to-methionine (K4M) mutation of histone H3.3 that inhibits H3K4 methylation, and the other carrying conditional double knockout of MLL3/4 enzymatic SET domains. Expression of H3.3K4M in lineage-specific precursor cells depletes H3K4 methylation and prevents adipogenesis and adipose tissue development. Mechanistically, H3.3K4M prevents enhancer activation in adipogenesis by destabilizing MLL3/4 proteins but not other Set1-like H3K4 methyltransferases. Notably, deletion of the enzymatic SET domain of MLL3/4 in lineage-specific precursor cells mimics H3.3K4M expression and prevents adipose tissue development. Interestingly, destabilization of MLL3/4 by H3.3K4M in adipocytes does not affect adipose tissue maintenance and function. Together, our findings indicate that H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development.


Author(s):  
Justin J. Rochford

Appropriately functioning adipose tissue is essential for human health, a fact most clearly illustrated by individuals with lipodystrophy, who have impaired adipose development and often suffer severe metabolic disease as a result. Humans with obesity display a similar array of metabolic problems. This reflects failures in fat tissue function in obesity, which results in consequences similar to those seen when insufficient adipose tissue is present. Thus a better understanding of the molecules that regulate the development of fat tissue is likely to aid the generation of novel therapeutic strategies for the treatment of all disorders of altered fat mass. Single gene disruptions causing lipodystrophy can give unique insights into the importance of the proteins they encode in human adipose tissue development. Moreover, the mechanisms via which they cause lipodystrophy can reveal new molecules and pathways important for adipose tissue development and function as well as confirming the importance of molecules identified from studies of cellular and animal models.


eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Tiziana Squillaro ◽  
Gianfranco Peluso ◽  
Umberto Galderisi ◽  
Giovanni Di Bernardo

Complex interaction between genetics, epigenetics, environment, and nutrition affect the physiological activities of adipose tissues and their dysfunctions, which lead to several metabolic diseases including obesity or type 2 diabetes. Here, adipogenesis appears to be a process characterized by an intricate network that involves many transcription factors and long noncoding RNAs (lncRNAs) that regulate gene expression. LncRNAs are being investigated to determine their contribution to adipose tissue development and function. LncRNAs possess multiple cellular functions, and they regulate chromatin remodeling, along with transcriptional and post-transcriptional events; in this way, they affect gene expression. New investigations have demonstrated the pivotal role of these molecules in modulating white and brown/beige adipogenic tissue development and activity. This review aims to provide an update on the role of lncRNAs in adipogenesis and adipose tissue function to promote identification of new drug targets for treating obesity and related metabolic diseases.


2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Lenan Zhuang ◽  
Younghoon Jang ◽  
Young-Kwon Park ◽  
Ji-Eun Lee ◽  
Shalini Jain ◽  
...  

Pituitary ◽  
2003 ◽  
Vol 6 (2) ◽  
pp. 97-102 ◽  
Author(s):  
David J. Flint ◽  
Nadine Binart ◽  
John Kopchick ◽  
Paul Kelly

2015 ◽  
Vol 54 (3) ◽  
pp. 263-275 ◽  
Author(s):  
Jacqueline M Wallace ◽  
John S Milne ◽  
Raymond P Aitken ◽  
Dale A Redmer ◽  
Lawrence P Reynolds ◽  
...  

Low birthweight is a risk factor for neonatal mortality and adverse metabolic health, both of which are associated with inadequate prenatal adipose tissue development. In the present study, we investigated the impact of maternal undernutrition on the expression of genes that regulate fetal perirenal adipose tissue (PAT) development and function at gestation days 89 and 130 (term=145 days). Singleton fetuses were taken from adolescent ewes that were either fed control (C) intake to maintain adiposity throughout pregnancy or were undernourished (UN) to maintain conception weight but deplete maternal reserves (n=7/group). Fetal weight was independent of maternal intake at day 89, but by day 130, fetuses from UN dams were 17% lighter and had lower PAT mass that contained fewer unilocular adipocytes. Relative PAT expression ofIGF1,IGF2,IGF2Rand peroxisome proliferator-activated receptor gamma (PPARG) mRNA was lower in UN than in controls, predominantly at day 89. Independent of maternal nutrition, PAT gene expression ofPPARG, glycerol-3-phosphate dehydrogenase, hormone sensitive lipase, leptin, uncoupling protein 1 and prolactin receptor increased, whereasIGF1,IGF2,IGF1RandIGF2Rdecreased between days 89 and 130. Fatty acid synthase and lipoprotein lipase (LPL) mRNAs were not influenced by nutrition or stage of pregnancy. Females had greaterLPLand leptin mRNA than males, andLPL, leptin andPPARGmRNAs were decreased in UN at day 89 in females only. PAT gene expression correlations with PAT mass were stronger at day 89 than they were at day 130. These data suggest that the key genes that regulate adipose tissue development and function are active beginning in mid-gestation, at which point they are sensitive to maternal undernutrition: this leads to reduced fetal adiposity by late pregnancy.


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