Rosiglitazone remodels the lipid droplet and britens human visceral and subcutaneous adipocytes ex vivo

Abstract

White adipocytes are specialized cells that have a very high capacity to esterify and store FAs as triglyceride (TAG) within a single lipid droplet (LD) and release them as required by variations in nutritional state (1). In obesity, the adipocyte must cope with an increased flux of FAs from the diet and higher basal lipolysis (2, 3). If these FAs are not efficiently esterified or oxidized, unbound FAs within the cell cause lipotoxic stress with deleterious consequences for adipocyte metabolic and endocrine function (4-6). As the storage capacity of the adipocyte is exceeded in obesity, the overflow of FAs can lead to ectopic fat deposition and systemic metabolic dysfunction (1,7,8). Strategies to modify the metabolism of FAs in adipocytes have therapeutic potential in obesity-related metabolic diseases.In contrast to multilocular brown or "brite"/beige adipocytes that are densely packed with mitochondria and express UCP1, white adipocytes contain relatively few mitochondria, low FA oxidation capacity, and much lower levels of UCP1 (9). White adipose tissue (WAT), however, can acquire brown-like features in response to -adrenergic stimulation or cold. Studies in rodents have shown that brite/beige adipocytes can be formed from mature white adipocytes (10, 11) or the recruitment and differentiation of beige progenitors (12,13). Several lines of evidence indicate that mature white human adipocytes can be metabolically reprogrammed to a more oxidative phenotype in Abstract Treatment with PPAR agonists in vivo improves human adipocyte metabolism, but the cellular mechanisms and possible depot differences in responsiveness to their effects are poorly understood. To examine the ex vivo metabolic effects of rosiglitazone (Rosi), we cultured explants of human visceral (omental) and abdominal subcutaneous adipose tissues for 7 days. Rosi increased mRNA levels of transcriptional regulators of brite/beige adipocytes (PGC1, PRDM16), triglyceride synthesis (GPAT3, DGAT1), and lipolysis (ATGL) similarly in adipose tissues from both depots. In parallel, Rosi increased key modulators of FA oxidation (UCP1, FABP3, PLIN5 protein), rates of FA oxidation, and protein levels of electron transport complexes, suggesting an enhanced respiratory capacity as confirmed in newly differentiated adipocytes. Rosi led to the formation of small lipid droplets (SLDs) around the adipocyte central lipid droplet; each SLD was decorated with redistributed mitochondria that colocalized with PLIN5. SLD maintenance required lipolysis and FA reesterification. Rosi thus coordinated a structural and metabolic remodeling in adipocytes from both visceral and subcutaneous depots that enhanced oxidative capacity. Selective targeting of these cellular mechanisms to improve adipocyte FA handling may provide a new approach to treat metabolic complications of obesity and diabetes.-Lee, M-J., S. Jash, J. E. C. Jones, V. Puri, and S. K. Fried. Rosiglitazone remodels the lipid droplet and britens human visceral and subcutaneous adipocytes ex vivo. J. Lipid Res. 20...

Inhibition of miR-27b Regulates Lipid Metabolism in Skeletal Muscle of Obese Rats During Hypoxic Exercise by Increasing PPARγ Expression

“…MiR-27b/PPARγ pathway can regulate lipid metabolism and both ATGL and LPL are shown to accelerate TG hydrolysis to release fatty acids for oxidation ( Schoonjans et al, 1996 ; Lee et al, 2019 ). It is reported that miR-27b could inhibit LPL mRNA expression, while PPARγ regulated the mRNA expression of ATGL and LPL ( Schoonjans et al, 1996 ; Kershaw et al, 2007 ; Karbiener et al, 2009 ; Lee et al, 2019 ). Therefore, miR-27b/PPARγ pathway may affect ATGL and LPL mRNA expression, which in turn causes protein expression changes of these genes.…”

Surface-associated lipid droplets: an intermediate site for lipid transport in human adipocytes?

“…This is in agreement with previous reports, addressing a similar lipid droplet phenotype to represent sites of lipolysis [ 18 , 21 ]. Also, the significance of these lipid droplet compartments is supported by Lee M-J et al, which detected small lipid droplets (SLDs) in human adipocytes following Rosiglitazone-treatment [ 19 ]. In contrast to our observation, SLDs were only visible in Rosiglitazone-treated cells, whereas we find a similar phenotype independent of treatment.…”

“…To our knowledge, only few reports have previously reported a similar lipid droplet phenotype in primary adipocytes. Lipid droplet patches were suggested to resemble sites of lipolysis [ 18 ], and small lipid droplets, decorated with mitochondria, was proposed to form following Rosiglitazone treatment [ 19 , 20 ]. Further, tiny microlipid droplets (<1 μm in diameter) were formed close to the cell surface following acute adrenergic stimulation [ 21 ].…”

Indomethacin promotes browning and brown adipogenesis in both murine and human fat cells

“…Rosi and other thiazolidinedione (TZD) analogs have been used as insulin‐sensitizing drugs in the treatment of type 2 diabetes mellitus (T2DM) 16 . Rosi is commonly used in cell culture to promote adipogenesis as well as induce browning of white adipocytes 17‐20 . It is postulated that Rosi's browning effect is a result of its PPARγ‐agonist activity 18,21 .…”