Metabolic remodeling of white adipose tissue in obesity

Abstract

Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower V̇(O₂), V̇(CO₂), and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity.

Adipose cell hypertrophy precedes the appearance of small adipocytes by 3 days in C57BL/6 mouse upon changing to a high fat diet

“…2 If adipose tissue cannot store ingested caloric excess, insulin action and normal metabolic flexibility of energy homeostasis is impacted negatively. 3 Thus, understanding the dynamic response of adipose tissue to changes in diet has attracted attention, 4 especially in the context of the ongoing worldwide increase in obesity and resulting public health issues. Short-term overfeeding has been associated with reduced locomotor activity which contributes to net weight gain, 5 adipose tissue lipid overload, 6 and adipose cell specific effects including impaired insulin signaling at the IRS-1 7 level but maintained lipolytic rate.…”

Insights into an adipocyte whitening program

“…Results of metabolomic analyses, adipose tissue respirometry, electron microscopy, and expression analyses of key genes and proteins important for adipocyte metabolism showed evidence of dysregulation of metabolic pathways, loss of mitochondrial biogenetic capacity, mitochondrial remodeling, and activation of mitophagy. 4 We propose that these findings demonstrate the presence of a "whitening" program (as opposed to the more commonly considered "browning" program) that occurs in adipocytes under conditions of chronic nutrient excess. the work as finished as possible, to cover up all the tracks, to not worry about blind alleys or describe how you had the wrong idea first, and so on.…”

“…4 Key changes in lipid pathways were apparent, with increases in the inflammatory mediator 12-HETE as well as most metabolites in the arachidonate synthesis pathway occurring in adipose tissues from high fatfed mice. Other biochemical evidence for adipocyte inflammation included an increase in cholesterol and osmolytes, both of which could activate the inflammasome.…”

“…However, upon six weeks of high fat feeding, we found little evidence of infiltrating macrophages in adipose tissue, despite near maximal increases in adipocyte size and the development of systemic glucose intolerance, insulin intolerance, and hyperinsulinemia. 4 Thus, we chose six weeks of high fat feeding as the model to study adipocyte metabolism because it provided a model of near maximal adipocyte hypertrophy occurring in the context of obesity in the relative absence of infiltrating inflammatory cells (Fig. 1A).…”

“…By 12 weeks of high fat diet, there were extensive decreases in the abundance of multiple mitochondrial matrix and electron transport chain proteins. 4 Collectively, this information enables construction of a new working model of how adipocyte metabolism remodels under conditions of nutrient excess. We posit that once an adipocyte reaches near maximal size, a coordinated adipocyte "whitening" program is triggered.…”