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Objective: Transcriptomic analysis of gene expression in brown adipose tissue (BAT) from mice in response to cold revealed strong induction of growth and differentiation factor 15 (GDF15). This study aimed to characterize GDF15 as a brown adipokine released in response to thermogenic activation and to determine its target functions.Methods: GDF15 expression was measured in adipose tissues from mice in response to physiological and pharmacological modulators of thermogenesis. Brown and beige cell cultures were used to dissect the mechanisms regulating GDF15 expression. Brown adipocyte cellular models of fibroblast growth factor 21 and β-klotho invalidation were employed to identify the autocrine regulators of GDF15. RAW 264.7 macrophages were used to explore the targeting of GDF15 released by brown adipocytes.Results: Cold exposure of mice strongly induced GDF15 expression in BAT. Norepinephrine and cyclic adenosine monophosphate induced GDF15 expression and release by cells through protein kinase A-mediated mechanisms. Noradrenergic regulation of GDF15 required the active fibroblast growth factor 21 pathway in brown adipocytes. GDF15 released by brown adipocytes targeted macrophages and downregulated the expression of proinflammatory genes.Conclusions: GDF15 is a brown adipokine released by brown and beige cells in response to thermogenic activity. GDF15 released by BAT targets macrophages and may mediate downregulation of local inflammatory pathways. [ABSTRACT FROM AUTHOR] more...

Abstract: Fibroblast growth factor 21 (FGF21) has been proposed to be an antiaging hormone on the basis of experimental studies in rodent models. However, circulating FGF21 levels are increased with aging in rodents and humans. Moreover, despite the metabolic health‐promoting effects of FGF21, the levels of this hormone are increased under conditions such as obesity and diabetes, an apparent incongruity that has been attributed to altered tissue responsiveness to FGF21. Here, we investigated serum FGF21 levels and expression of genes encoding components of the FGF21‐response molecular machinery in adipose tissue from healthy elderly individuals (≥70 years old) and young controls. Serum FGF21 levels were increased in elderly individuals and were positively correlated with insulinemia and HOMA‐IR, indices of mildly deteriorated glucose homeostasis. Levels of β‐Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor‐1 levels were unaltered. Moreover, total ERK1/2 protein levels were decreased in elderly individuals in association with an increase in the ERK1/2 phosphorylation ratio relative to young controls. Adipose explants from aged and young mice respond similarly to FGF21 “ex vivo”. Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21‐responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies. [ABSTRACT FROM AUTHOR] more...

Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) in the diet protect against insulin resistance and obesity. Fibroblast growth factor-21 (Fgf21) is a hormonal factor released mainly by the liver that has powerful anti-diabetic effects. Here, we tested whether the beneficial metabolic effects of LC n-3 PUFA involve the induction of Fgf21. C57BL/6 J mice were exposed to an obesogenic, corn-oil-based, high-fat diet (cHF), or a diet in which corn oil was replaced with a fish-derived LC n-3 PUFA concentrate (cHF + F) using two experimental settings: short-term (3 weeks) and long-term treatment (8 weeks). CHF + F reduced body weight gain, insulinemia, and triglyceridemia compared to cHF. cHF increased plasma Fgf21 levels and hepatic Fgf21 gene expression compared with controls, but these effects were less pronounced or absent in cHF + F-fed mice. In contrast, hepatic expression of peroxisome proliferator-activated receptor (PPAR)-α target genes were more strongly induced by cHF + F than cHF, especially in the short-term treatment setting. The expression of genes encoding Fgf21, its receptors, and Fgf21 targets was unaltered by short-term LC n-3 PUFA treatment, with the exception of Ucp1 (uncoupling protein 1) and adiponectin genes, which were specifically up-regulated in white fat. In the long-term treatment setting, the expression of Fgf21 target genes and receptors was not differentially affected by LC n-3 PUFA. Collectively, our findings indicate that increased Fgf21 levels do not appear to be a major mechanism through which LC n-3 PUFA ameliorates high-fat-diet-associated metabolic disorders. [ABSTRACT FROM AUTHOR] more...

The article discusses the role of mitochondrial deoxyribonucleic acid (mtDNA) in white adipose tissue pathology. In mammals, mtDNA functions by encoding proteins of the respiratory chain/oxidative phosphorylation system (OXPHOS) along with other parts of the mitochondrial translation system. Research have emphasized the importance of mitochondrial biogenesis in white adipose tissue and the possibility for mitochondrial changes to disturb white adipocyte development and function. more...

PPARγ is a ligand-dependent master transcription factor controlling adipocyte differentiation as well as multiple biological processes taking place in other cells present in adipose tissue depots such as macrophages. Recent research indicates that HIV-1 infection-related events may alter adipose tissue biology through several mechanisms involving PPARγ, ranging from direct effects of HIV-1-encoded proteins on adipocytes to the promotion of a proinflammatory environment that interferes with PPARγ actions. This effect of HIV-1 on adipose tissue cells can occur even in the absence of direct infection of adipocytes, as soluble HIV-1-encoded proteins such as Vpr may enter cells and inhibit PPARγ action. Moreover, repression of PPARγ actions may relieve inhibitory pathways of HIV-1 gene transcription, thus enhancing HIV-1 effects in infected cells. HIV-1 infection-mediated interference of PPARγ-dependent pathways in adipocytes and other cells inside adipose depots such as macrophages is likely to create an altered local environment that, after antiretroviral treatment, leads to lipodystrophy in HIV-1-infected and HAART-treated patients. [ABSTRACT FROM AUTHOR] more...

Uncoupling proteins (UCPs) are mitochondrial membrane transporters involved in the control of energy conversion in mitochondria. Experimental and genetic evidence relate dysfunctions of UCPs with metabolic syndrome and obesity. The PPAR subtypes mediate to a large extent the transcriptional regulation of the UCP genes, with a distinct relevance depending on the UCP gene and the tissue in which it is expressed. UCP1 gene is under the dual control of PPARγ and PPARα in relation to brown adipocyte differentiation and lipid oxidation, respectively. UCP3 gene is regulated by PPARα and PPARδ in the muscle, heart, and adipose tissues. UCP2 gene is also under the control of PPARs even in tissues in which it is the predominantly expressed UCP (eg, the pancreas and liver). This review summarizes the current understanding of the role of PPARs in UCPs gene expression in normal conditions and also in the context of type-2 diabetes or obesity. [ABSTRACT FROM AUTHOR] more...

Abstract: Lithium impairs the appearance of the characteristic morphology of brown adipocytes and downregulates the expression of marker genes of brown adipocyte differentiation. These effects are dose-dependent and are more pronounced when exposure of preadipocytes to lithium is initiated at early stages of differentiation. Although lithium reduces the expression of genes common to both white and brown adipocytes [fatty acid binding protein aP2 (aP2/FABP) or peroxisome proliferating activated receptor γ], genes expressed differentially in brown adipocytes, i.e., uncoupling protein 1, PPAR gamma coactivator-1α, and peroxisome proliferating activated receptor α, are particularly sensitive to lithium treatment-dependent downregulation. Brown adipocytes appear as preferential targets of the inhibitory action of lithium on adipocyte differentiation. [Copyright &y& Elsevier] more...

The phytol derivatives phytanic acid and pristanic acid may activate nuclear hormone receptors and influence gene expression and cell differentiation. Phytanic acid induces brown adipocyte differentiation. It was determined that brown fat and brown adipocytes are sites of high gene expression of phytanoyl-CoA hydroxylase, the enzyme required for initiation of peroxisomal α-oxidation of phytanic acid. However, the effects of phytanic acid were not mediated by its α-oxidation product pristanic acid, which did not promote brown adipocyte differentiation or stimulate transcription of the uncoupling protein-1 gene. Moreover, acute cold exposure of mice caused a dramatic mobilization of the phytanic acid stores in brown adipose tissue thus suggesting that a high local exposure to phytanic acid in brown fat may contribute to signalling adaptive changes in the tissue in response to thermogenic activation. [Copyright &y& Elsevier] more...

We have performed a sequential study on the abundance of the mRNA for uncoupling protein (UCP), subunit II of cytochrome-c oxidase (COII) and lipoprotein lipase in brown adipose tissue during the fetal and postnatal periods. Moreover, we have determined whether these parameters can be modulated by ambient temperature in the early hours after birth, and at which point in development this sensitivity first appears. UCP gene expression in the fetal and neonatal period has particular features when compared with overall mitochondriogenesis (COII mRNA expression) or with the expression of lipoprotein lipase mRNA. There is a specific induction of UCP gene expression between days 18 and 19 of pregnancy followed by a specific increase of UCP gene expression in utero and a further increase after birth. The acquisition of the physiological apparatus capable of the response to UCP and lipoprotein lipase gene expression to the environmental temperature is not achieved until the last day of fetal development. This result suggests that mechanisms of β-adrenergic modulation of gene expression in brown fat are already established at birth. From an experiment on iopanoic acid treatment of pregnant mothers, it was concluded that iodothyronine 5'-deiodinase activity is not necessary for the expression of the mRNAs for UCP, COII and lipoprotein lipase in the fetus whereas it is necessary for the acquisition of temperature sensitivity to these parameters at birth. [ABSTRACT FROM AUTHOR] more...