Uncoupling Protein 3 and Peroxisome Proliferator-Activated Receptor γ2 Contribute to Obesity and Diabetes in Palauans

Uncoupling protein-3 (UCP3) is a member of the mitochondrial carrier family expressed preferentially in skeletal muscle and heart. It appears to be involved in metabolic handling of fatty acids in a way that minimizes excessive production of reactive oxygen species. Fatty acids are powerful regulators of UCP3 gene transcription. We have found that the role of peroxisome proliferator-activated receptor-α (PPARα) on the control of UCP3 gene expression depends on the tissue and developmental stage. In adults, UCP3 mRNA expression is unaltered in skeletal muscle from PPARα-null mice both in basal conditions and under the stimulus of starvation. In contrast, UCP3 mRNA is down-regulated in adult heart both in fed and fasted PPARα-null mice. This occurs despite the increased levels of free fatty acids caused by fasting in PPARα-null mice. In neonates, PPARα-null mice show impaired UCP3 mRNA expression in skeletal muscle in response to milk intake, and this is not a result of reduced free fatty acid levels. The murine UCP3 promoter is activated by fatty acids through either PPARα or PPARδ but not by PPARγ or retinoid X receptor alone. PPARδ-dependent activation could be a potential compensatory mechanism to ensure appropriate expression of UCP3 gene in adult skeletal muscle in the absence of PPARα. However, among transcripts from other PPARα and PPARδ target genes, only those acutely induced by milk intake in wild-type neonates were altered in muscle or heart from PPARα-null neonates. Thus, PPARα-dependent regulation is required for appropriate gene regulation of UCP3 as part of the subset of fatty-acid-responsive genes in neonatal muscle and heart.

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Up-regulation of uncoupling protein 3 by thyroid hormone, peroxisome proliferator-activated receptor ligands and 9-cis retinoic acid in L6 myotubes

FEBS Letters ◽

10.1016/s0014-5793(99)01477-5 ◽

1999 ◽

Vol 461 (3) ◽

pp. 319-322 ◽

Cited By ~ 57

Author(s):

Itsuro Nagase ◽

Shigeru Yoshida ◽

Xavier Canas ◽

Yukiko Irie ◽

Kazuhiro Kimura ◽

...

Keyword(s):

Retinoic Acid ◽

Thyroid Hormone ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Receptor Ligands ◽

Peroxisome Proliferator Activated Receptor ◽

L6 Myotubes ◽

Uncoupling Protein 3

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Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator–activated receptor α

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013700 ◽

2020 ◽

Vol 295 (29) ◽

pp. 9804-9822 ◽

Cited By ~ 10

Author(s):

Darren M. Gordon ◽

Kari L. Neifer ◽

Abdul-Rizaq Ali Hamoud ◽

Charles F. Hawk ◽

Andrea L. Nestor-Kalinoski ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Target Genes ◽

Uncoupling Protein ◽

Mitochondrial Activity ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Obesity And Diabetes ◽

Selective Ligand ◽

Related Proteins

Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator–activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.

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Clinical Application Potential of Small Molecules that Induce Brown Adipose Tissue Thermogenesis by Improving Fat Metabolism

Cell Transplantation ◽

10.1177/0963689720927394 ◽

2020 ◽

Vol 29 ◽

pp. 096368972092739

Author(s):

Kang-Yun Lu ◽

Kingsley Theras Primus Dass ◽

Sheng-Feng Tsai ◽

Hong-Meng Chuang ◽

Shinn-Zong Lin ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Adenosine Monophosphate ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Computed Tomography Images ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Treatment Of Obesity

Mammalian fat comprises white and brown adipose tissue (WAT and BAT, respectively). WAT stores energy, whereas BAT is used for thermogenesis. In recent years, the incidence of obesity and its associated disorders have increased tremendously. Considering the thermogenic capacity and decreased levels of BAT with increasing age, BAT can be used as a suitable therapeutic target for the treatment of obesity and diabetes. In several studies, using positron emission tomography and computed tomography images, adult humans have been shown to have functional BAT in interscapular fat. Results of these basic research studies on BAT have shed light on the new components of transcriptional regulation and the role of hormones in stimulating BAT growth and differentiation. In this review article, we have summarized the thermogenic regulators identified in the past decades by focusing on peroxisome proliferator-activated receptor gamma/uncoupling protein 1 activators, branched-chain amino acids, fatty acids (lipokine), and adenosine monophosphate-activated protein kinase mediators. We have also presented the progress of a few ongoing clinical trials aimed at the treatment of obesity and its associated metabolic disorders. The main purpose of this review was to provide a comprehensive introduction to the latest knowledge of the representative thermogenic regulators for the treatment of obesity. The fat combustion capacity of BAT may have great potential and can be considered as a suitable target for the therapeutic application of drugs from bench-to-bed treatment of obesity and the associated diseases.

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Pancreatic Islet Adaptation to Fasting Is Dependent on Peroxisome Proliferator-Activated Receptor α Transcriptional Up-Regulation of Fatty Acid Oxidation

Endocrinology ◽

10.1210/en.2004-0667 ◽

2005 ◽

Vol 146 (1) ◽

pp. 375-382 ◽

Cited By ~ 71

Author(s):

Sandrine Gremlich ◽

Christopher Nolan ◽

Raphaël Roduit ◽

Rémy Burcelin ◽

Marie-Line Peyot ◽

...

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Pancreatic Islet ◽

Cellular Response ◽

Uncoupling Protein ◽

Acid Oxidation ◽

Hyperinsulinemic Hypoglycemia ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

The cellular response to fasting and starvation in tissues such as heart, skeletal muscle, and liver requires peroxisome proliferator-activated receptor-α (PPARα)-dependent up-regulation of energy metabolism toward fatty acid oxidation (FAO). PPARα null (PPARαKO) mice develop hyperinsulinemic hypoglycemia in the fasting state, and we previously showed that PPARα expression is increased in islets at low glucose. On this basis, we hypothesized that enhanced PPARα expression and FAO, via depletion of lipid-signaling molecule(s) for insulin exocytosis, are also involved in the normal adaptive response of the islet to fasting. Fasted PPARαKO mice compared with wild-type mice had supranormal ip glucose tolerance due to increased plasma insulin levels. Isolated islets from the PPARα null mice had a 44% reduction in FAO, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion. In normal rats, fasting for 24 h increased islet PPARα, carnitine palmitoyltransferase 1, and uncoupling protein-2 mRNA expression by 60%, 62%, and 82%, respectively. The data are consistent with the view that PPARα, via transcriptionally up-regulating islet FAO, can reduce insulin secretion, and that this mechanism is involved in the normal physiological response of the pancreatic islet to fasting such that hypoglycemia is avoided.

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