White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways

Abstract

ObjectiveFat depots with thermogenic activity have been identified in humans. In mice, the appearance of thermogenic adipocytes within white adipose depots (so-called brown-in-white i.e., brite or beige adipocytes) protects from obesity and insulin resistance. Brite adipocytes may originate from direct conversion of white adipocytes. The purpose of this work was to characterize the metabolism of human brite adipocytes.MethodsHuman multipotent adipose-derived stem cells were differentiated into white adipocytes and then treated with peroxisome proliferator-activated receptor (PPAR)γ or PPARα agonists between day 14 and day 18. Gene expression profiling was determined using DNA microarrays and RT-qPCR. Variations of mRNA levels were confirmed in differentiated human preadipocytes from primary cultures. Fatty acid and glucose metabolism was investigated using radiolabelled tracers, Western blot analyses and assessment of oxygen consumption. Pyruvate dehydrogenase kinase 4 (PDK4) knockdown was achieved using siRNA. In vivo, wild type and PPARα-null mice were treated with a β3-adrenergic receptor agonist (CL316,243) to induce appearance of brite adipocytes in white fat depot. Determination of mRNA and protein levels was performed on inguinal white adipose tissue.ResultsPPAR agonists promote a conversion of white adipocytes into cells displaying a brite molecular pattern. This conversion is associated with transcriptional changes leading to major metabolic adaptations. Fatty acid anabolism i.e., fatty acid esterification into triglycerides, and catabolism i.e., lipolysis and fatty acid oxidation, are increased. Glucose utilization is redirected from oxidation towards glycerol-3-phophate production for triglyceride synthesis. This metabolic shift is dependent on the activation of PDK4 through inactivation of the pyruvate dehydrogenase complex. In vivo, PDK4 expression is markedly induced in wild-type mice in response to CL316,243, while this increase is blunted in PPARα-null mice displaying an impaired britening response.ConclusionsConversion of human white fat cells into brite adipocytes results in a major metabolic reprogramming inducing fatty acid anabolic and catabolic pathways. PDK4 redirects glucose from oxidation towards triglyceride synthesis and favors the use of fatty acids as energy source for uncoupling mitochondria.

Cinnamaldehyde induces fat cell-autonomous thermogenesis and metabolic reprogramming

“…We observed that chronic CA treatment upregulates the expression of lipolytic genes ( Hsl, Atgl), key regulators in fatty acid oxidation ( Cpt1b, Ppara ), lipogenic genes ( Gyk, Dgat1 ) , and Pdk4 , an enzyme that enhances lipid metabolism and has recently been reported to be responsible for major metabolic adaptations during white-to-beige conversion of human adipocytes (Fig. 2J, L, and M) [13]. Increased oxidative metabolism in mitochondria is known to be accompanied by increased reactive oxygen species (ROS) production.…”

Brown and Beige Adipose Tissues in Health and Disease

“…Interestingly, cold exposure increases expression of genes responsible for replenishing lipid droplets in BAT, including the genes that mediate glucose uptake, lipogenesis, and TAG synthesis ( Glut1 , Glut4 , hexokinase , PFK1 , PDHa1 , FAS , glycerol kinase, PEPCK , GPAT3 , Dgat1 , Dgat2 ) (166). PPARα or PPARγ agonists, which promote differentiation of human mesenchymal stem cells into brown/beige adipocytes, also stimulate expression of genes responsible for lipolysis, de novo lipogenesis, TAG synthesis, and lipid droplet formation (16). Therefore, lipid droplet dynamics, including lipid droplet lipolysis and replenishment, are likely to play an important role in regulating BAT and beige fat thermogenesis.…”

“…Interestingly, PPARγ agonists potently increase de novo beige adipogenesis and white-to-beige adipocyte transdifferentiation in both rodents and humans (16, 188, 229, 239). The ability of PPARγ to stimulate preadipocyte differentiation into either white or brown/beige adipocytes appears to be determined by its associated coactivators.…”

Brown Adipose Tissue: an Update on Recent Findings

“…The action of browning WAT into BAT-like adipocytes, or beige (“brite”) cells, has been further postulated to protect against obesity via body fat reduction and related complications [32–35, 31, 36, 37]. Similar to BAT adipocytes, beige adipocytes have the ability to take on a BAT-like thermogenic phenotype in response to various stimuli such as cold, endocrine factors or chemical compounds.…”