Metabolic switch during adipogenesis: From branched chain amino acid catabolism to lipid synthesis

Abstract

Fat cell metabolism has an impact on body homeostasis and its proper function. Nevertheless, the knowledge about simultaneous metabolic processes, which occur during adipogenesis and in mature adipocytes, is limited. Identification of key metabolic events associated with fat cell metabolism could be beneficial in the field of novel drug development, drug repurposing, as well as for the discovery of patterns predicting obesity risk. The main objective of our work was to provide comprehensive characterization of metabolic processes occurring during adipogenesis and in mature adipocytes. In order to globally determine crucial metabolic pathways involved in fat cell metabolism, metabolomics and transcriptomics approaches were applied. We observed significantly regulated metabolites correlating with significantly regulated genes at different stages of adipogenesis. We identified the synthesis of phosphatidylcholines, the metabolism of even and odd chain fatty acids, as well as the catabolism of branched chain amino acids (BCAA; leucine, isoleucine and valine) as key regulated pathways. Our further analysis led to identification of an enzymatic switch comprising the enzymes Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthase) and Auh (AU RNA binding protein/enoyl-CoA hydratase) which connects leucine degradation with cholesterol synthesis. In addition, propionyl-CoA, a product of isoleucine degradation, was identified as a putative substrate for odd chain fatty acid synthesis. The uncovered crosstalks between BCAA and lipid metabolism during adipogenesis might contribute to the understanding of molecular mechanisms of obesity and have potential implications in obesity prediction.

Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer

“…On the one hand, pyruvate can be transformed into acetyl CoA for citrate synthesis by the catalysis of PDH, 35 the expression of which was increased in PCTs. 38 Although additional in vitro or in vivo experiments were not performed to validate the functional consequence of our observed alterations, previous study revealed that altered BCAA metabolism drives cancer progression in myeloid leukaemia through the MSI2-BCAT1 axis. 49 It is noteworthy that the expression of BRP44 and BRP44L which encode the pyruvate transporters, was significantly elevated in PCTs, illustrating that enhanced pyruvate replenishment fuels the TCA cycle.…”

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

“…In accordance with our transcriptomic array data, both Hsp90β1 and Itgb7 were upregulated in PTLs compared to WT and GIT2KO thymus (Figure 4D, E: Tables S4, S5). A large proportion of this PTL-based dataset is strongly linked with metabolic aging and clock regulation [60, 61], cell senescence [62, 63] and age-related immune dysfunction [64] (Figure 4F). For each of the significantly-regulated PTL transcripts in these general categories (Figure 4F) it was evident that their regulation extent (z ratio magnitude) was consistently greater when compare to the dysfunctional GIT2KO thymus as opposed to the WT thymus.…”

“…HMGCS2 is one of the controlling enzymes in the mitochondrial mechanism of ketogenesis, an energy derivation process often entrained in the context of disrupted glucose metabolism and altered aging [49, 102]. HMGCS2 functionality is not only associated with ketogenesis but also with fatty acid β-oxidation, a compensatory process which is commonly observed in the context of disrupted aging mechanisms, age-related neurodegenerative conditions and age-related metabolic disruption [60, 78, 124]. Confirming our observations of disrupted Troma-I expression in the GIT2KO model it has also been demonstrated that reductions in Troma-I can also modulate HMGCS2 expression and in doing so modulate energy metabolism and ketogenic activity [103].…”

Lipid droplet growth: regulation of a dynamic organelle

“…Examination of a 3T3-L1 adipocyte differentiation gene expression profile dataset [45] reveals dynamic changes in the levels of genes encoding LD-associated proteins (Fig. 2).…”