Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype

Flachs, Pavel; Adamcová, Kateřina; Zouhar, Petr; Marques, Cátia; Janovská, Petra; Viegas, Iván; Jones, John G.; Bardová, Kristina; Svobodová, Michaela; Hansikova, Jana; Kuda, Ondřej; Rossmeisl, Martin; Liisberg, Ulrike; Borkowska, Andzelika; Kristiansen, Karsten; Madsen, Lise; Kopecký, Jan

doi:10.1038/ijo.2016.228

Cited by 44 publications

(60 citation statements)

References 56 publications

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“…These trends were resolved with thermoneutral housing, demonstrating that lipogenesis was upregulated by chronic cold stress. Indeed, the cold-dependency of this phenotype in UCP1 / mice is consistent with previous studies evaluating lipid response to long-term cold exposure (41,42). GLUT4 and Chrebp-, a transcription factor isoform known to be activated by glucose-mediated stimulation of CHREBP- (43), were highly upregulated and further studies will shed light on the requirement of this transcription factor in cold-induced lipogenesis.…”

Section: Discussionsupporting

confidence: 89%

UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver

Bond

Ntambi

2018

Journal of Lipid Research

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Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency. Defects in UCP1 and brown adipose tissue thermogenesis subject animals to chronic cold stress and elicit compensatory responses to generate heat. How UCP1 regulates white adipose tissue (WAT) lipid biology and tissue crosstalk is not completely understood. Here, we probed the effect of UCP1 deficiency on FA metabolism in inguinal and epididymal WAT and investigated how these metabolic perturbations influence hepatic lipid homeostasis. We report that at standard housing temperature (21°C), loss of UCP1 induces inguinal WAT de novo lipogenesis through transcriptional activation of the lipogenic gene program and elevated GLUT4. Inguinal adipocyte hyperplasia and depot expansion accompany the increase in lipid synthesis. We also found that UCP1 deficiency elevates adipose stearoyl-CoA desaturase gene expression, and increased inguinal WAT lipolysis supports the transport of adipose-derived palmitoleate (16:1n7) to the liver and hepatic triglyceride accumulation. The observed WAT and liver phenotypes were resolved by housing animals at thermoneutral housing (30°C). These data illustrate depot-specific responses to impaired BAT thermogenesis and communication between WAT and liver in UCP1 mice.

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Section: Discussionsupporting

confidence: 89%

UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver

Bond

Ntambi

2018

Journal of Lipid Research

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“…FGF21-dependent browning in DIO resistant UCP1 KO mice also raises the question on alternative thermogenic mechanisms. The simultaneous induction of lipolysis and lipogenesis fuels the idea of lipid futile cycling as an ATP-dependent thermogenic mechanism [49][50][51] , which may serve to maintain the lean phenotype of the UCP1 KO mouse. Other recently suggested mechanisms, such as creatine and calcium futile cycling 40,41 , were induced in cold-acclimated UCP1 KO mice but the pronounced induction of gene expression was not seen in this study.…”

Section: Discussionmentioning

confidence: 99%

Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

et al. 2020

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Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acylcarnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1.

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“…This demand likely included the ATP needed for FA synthesis and activation for TAG synthesis. The cycle of TAG breakdown and resynthesis consumes ATP and can be considered as a "futile cycle" that is reported to occur in rodent WAT in response to thiazolidinediones (52) or cold exposure (53), providing an adaptive mechanism to fine tune metabolic control (54). These conclusions are restricted to primary cultures of differentiated adipocytes from ASAT.…”

Section: Discussionmentioning

confidence: 99%

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

Lee¹,

Jash²,

Jones³

et al. 2019

Journal of Lipid Research

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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...

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Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype

Cited by 44 publications

References 56 publications

UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver

UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver

Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

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

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