Abstract
The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.
Highlights
Obesity is characterized by excess white adipose tissue (WAT) mass and is linked to complications such as insulin resistance, type 2 diabetes, cardiovascular disease and many common cancers[1,2]
Following carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-titration experiments, we found that the oxygen consumption rate (OCR) was increased following CKB knockdown (Fig. 3a and Extended Data Fig. 3a); this effect was accompanied by increased mitochondrial adenosine triphosphate (ATP) production and cellular ATP/adenosine diphosphate (ADP) ratio (Fig. 3b,c and Extended Data Fig. 3b), while mitochondrial abundance and morphology remained unchanged (Extended Data Fig. 3c–f)
Our results indicate that the effects of both siCKB and phosphocreatine incubations on CCL2 expression converge on increases in the ATP/ADP ratio, while alterations in mitochondrial activity are only linked to CKB depletion
Summary
Obesity is characterized by excess white adipose tissue (WAT) mass and is linked to complications such as insulin resistance, type 2 diabetes, cardiovascular disease and many common cancers[1,2]. At the white adipocyte level, obesity perturbs multiple processes, including gene transcription and metabolic pathways and promotes a pro-inflammatory phenotype, alterations which together link obesity to many of its sequelae[3,4,5,6]. Studies in immune cells demonstrate that alterations in intracellular metabolism are tightly coupled to inflammatory status[11,12] This demonstrates that metabolites can coordinate multiple cellular processes and that disturbances in their levels induce distinct changes in tissue function. The metabolic changes that characterize human obese WAT and how these impact on white adipocyte function and clinical phenotypes are unclear. To identify pathways disturbed in conditions of excess fat mass, we performed unbiased metabolomic and transcriptomic analyses of human WAT and identified that phosphocreatine/creatine metabolism is perturbed in obesity. Together with recent studies in beige/brown adipocytes[14,15,16,17] and macrophages[18], our findings highlight the unique cell type-selective role of the phosphocreatine/creatine pathway and its importance in the regulation of obesity-accelerated inflammation in WAT
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