An obesogenic diet impairs uncoupled substrate oxidation and promotes whitening of the brown adipose tissue in rats

Abstract

Brown adipose tissue (BAT) is rich in mitochondria containing uncoupling protein 1 (UCP1), and dissipates energy through thermogenesis. However, even though BAT mass and its UCP1 content increase in rodents chronically fed a high‐fat sucrose‐enriched (HFS) diet, marked expansion of adiposity still occurs in these animals, suggesting insufficient BAT‐mediated HFS diet‐induced thermogenesis. Thus, the objective of this study was to investigate the metabolic and molecular mechanisms that regulate BAT thermogenesis in HFS‐induced obesity. To accomplish this, rats were fed either a standard chow or HFS diet for 8 weeks. Subsequently, glucose and fatty acid metabolism and the molecular mechanisms underlying these processes were assessed in freshly isolated primary BAT adipocytes. Despite increasing BAT mass and its UCP1 content, the HFS diet reduced uncoupled glucose and palmitate oxidation in BAT adipocytes. It also markedly diminished tyrosine hydroxylase content and lipolysis in these cells. Conversely, glucose uptake, lactate production, glycerol incorporation into lipids, palmitate incorporation into triacylglycerol (TAG), phosphoenolpyruvate carboxykinase and glycerol kinase levels, and lipoprotein lipase and cluster of differentiation 36 gene expression were increased. In summary, a HFS diet enhanced glyceroneogenesis and shifted BAT metabolism toward TAG synthesis by impairing UCP1‐mediated substrate oxidation and by enhancing fatty acid esterification in intact brown adipocytes. These adaptive metabolic responses to chronic HFS feeding attenuated BAT thermogenic capacity and favoured the development of obesity. Key points Despite increasing brown adipose tissue (BAT) mass and levels of thermogenic proteins such as peroxisome proliferator‐activated receptor γ coactivator 1α, carnitine palmitoyltransferase 1B and uncoupling protein 1 (UCP1), an obesogenic high‐fat sucrose‐enriched (HFS) diet attenuated uncoupled glucose and fatty acid oxidation in brown adipocytes. Brown adipocytes diverted glycerol and fatty acids toward triacylglycerol (TAG) synthesis by elevating the cellular machinery that promotes fatty acid uptake along with phosphoenolpyruvate carboxykinase and glycerol kinase levels. The HFS diet increased glucose uptake that supported lactate production and provided substrate for glyceroneogenesis and TAG synthesis in brown adipocytes. Impaired UCP‐1‐mediated thermogenic capacity and enhanced TAG storage in BAT adipocytes were consistent with reduced adipose triglyceride lipase and tyrosine hydroxylase levels in HFS diet‐fed animals.

From honeymoon to dysfunction: brown fat remodelling in obesity

“…Da Eira et al. (2022) support the notion that chronic exposure to HFS diets impairs UCP1‐mediated substrate oxidation, despite higher BAT mass and thermogenic‐related protein expression. A deeper understanding of the mechanisms triggered by an obesogenic stimulus, such as dietary pattern, provides insights into potential new targets for the manipulation of BAT and enhanced therapeutic interventions.…”

“…Research by da Eira et al. (2022), recently published in The Journal of Physiology , shows how brown adipocytes shift their metabolism away from thermogenic function towards anabolic signalling and energy storage as a result of chronically higher energy influx in obesity.…”

“…To test whether the higher expression of thermogenic proteins resulted in changes in substrate oxidation, da Eira et al. (2022) evaluated glucose and palmitate oxidation in brown adipocytes isolated from rats. The cells were evaluated under basal conditions, beta‐adrenergic stimulation, and ATP synthase inhibition.…”

“…Da Eira et al. (2022) showed that despite these acute thermogenic changes, chronic exposure to the HFS diet impairs the lipolytic machinery, and reduces tyrosine hydroxylase (TH), the main protein responsible for catalysing catecholamines synthesis. This in turn would indicate less production of noradrenaline (norepinephrine), which is known to be one of the primary stimulants for NST in brown adipocytes.…”

“…To archive this, mitochondria increase their function to enhance oxidative phosphorylation activity, increase the proton flux into the intermembrane space, and augment the proton gradient, consequently increasing UCP1 activation and thermogenesis. Research by da Eira et al (2022), recently published in The Journal of Physiology, shows how brown adipocytes shift their metabolism away from thermogenic function towards anabolic signalling and energy storage as a result of chronically higher energy influx in obesity.…”