Ucp1 Expression In White Adipose Tissue Research Articles

An immune‐neuron axis guides adipose tissue loss in cancer‐associated cachexia

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by weight loss due to the atrophy of adipose tissue and skeletal muscle. CAC occurs in almost 80% of neoplastic diseases and causes death in more than 20% of cancer patients. The underlying mechanisms of the disease are poorly understood and no effective treatment for CAC is currently available. Recently, we and others demonstrated that a phenotypic switch from white- to beige adipocytes, a phenomenon called browning, accompanies CAC and contributes to increased energy dissipation. However, detailed mechanisms underlying this white to beige transition in CAC remained elusive. Here we show that cachexigenic tumors cause the activation of a type 2 immune response in white adipose tissue (WAT), which is functionally intertwined with neuron outgrowth, beta-adrenergic activation, and subsequent WAT browning. Immunohistochemical- and whole-mount immunofluorescence analyses revealed enhanced peripheral sympathetic neuron projections in cachectic WAT of mice and human patients. Using peripheral dopamine beta-hydroxylase (DBH) deficient mice, we demonstrate that local production of catecholamines by intra-adipose tissue neurons is responsible for increased lipolysis and initiation of the browning process. In vitro studies revealed that the increase in neuron arborization is promoted by alternatively activated macrophages which generate a neuroprotective environment covering the neurotoxic proinflammatory signals produced by cachexigenic tumors. In accordance with this concept, tumor-bearing mice that lack the interleukin-4 receptor exhibited a diminished type-2 immune response, attenuated neuronal outgrowth, and reduced browning of WAT compared to tumor-bearing wild type mice. Overall, our findings indicate that an immune–sympathetic neuron crosstalk increases local catecholamine production, lipolysis, and UCP-1 expression in WAT, thereby contributing to energy dissipation, and adipose tissue loss in CAC.

Prenatal PPARα Activation Moved Forward Transient Browning of WAT at Neonates and Increased HFD-Induced UCP1 Expression in WAT of Male Mice at Adulthood

Abstract Objectives To test the hypothesis that prenatal administration of PPARα agonist clofibrate may increase the developmental beige adipocytes and permanently increased the browning capacity of white adipose tissue (WAT). Methods Pregnant C57BL/6 J mice received a basal diet, without (C) or with 0.5% clofibrate (CF, a PPARα agonist) throughout pregnancy. After parturition, only male offspring were used; all suckled their mothers (who were eating the C diet) and after weaning, they ate a standard chow diet for 4 wk, followed by a high-fat diet (HFD) for 5 wk. Results CF administration significantly increased the expression of PPARα and its target genes. CF elevated serum concentrations and hepatic expression of FGF21 (a thermogenic hormone) in fetuses, with a return to basal levels after CF withdrawal. At postnatal day 84 (P84), CF-offspring had significantly higher mRNA and protein levels of UCP1 in response to HFD in inguinal (iWAT) but not in visceral fats. Based on UCP1 levels in iWAT on P7, P14, and P21, the appearance of the transient brown-adipocyte phenotype seemed to be hastened by prenatal CF exposure. The mRNA level of UCP1 is peaked at P14 in CF-offspring, unlike C-offspring which peaked at P21. However, the mRNA level of beige cell markers (Cd137, Tmem26, Tbx1) maintained the same across this time window (P7–21). Microarray analysis of global gene expression in iWAT during this time window is conducting, as well as serum level of leptin, since leptin surge is essential to the formation of beige adipocytes during this time window. Conclusions Giving CF to pregnant mice programmed greater HFD-induced WAT browning in subcutaneous, but not in visceral fat, in their male offspring at adulthood. We foresee the transient browning of iWAT occurred at critical window may offer clues for elucidating this interesting phenomenon. Funding Sources Ministry of Science and Technology, Taiwan.

Hedgehog signaling in bone regulates whole-body energy metabolism through a bone-adipose endocrine relay mediated by PTHrP and adiponectin.

Bone plays a role in energy metabolism, but the interplay between bone and other organs in this process is not completely understood. Here, we show that upregulated Hh signaling in bones results in increased whole-body energy expenditure, white adipose tissue (WAT) browning, hypoglycemia and skeletal muscle atrophy. We found that Hh signaling induces PTHrP secretion from bones and causes WAT browning. Injection of PTHrP-neutralizing antibody attenuates WAT browning and improves the circulating blood glucose level while high-fat diet treatment only rescues hypoglycemia. Furthermore, bone-derived PTHrP stimulates adiponectin secretion in WAT and results in systemic increase of fatty acid oxidation and glucose uptake. Mechanistically, PTHrP activates both PKA/cAMP and Akt/Foxo pathways for Ucp1 expression in WAT. PTHrP couples adiponectin actions to activate the AMPK pathway in the skeletal muscles and liver, respectively, for fatty acid oxidation. Our findings establish a new bone-adipose hormonal relay that regulates whole-body energy metabolism.

Osteocyte-Secreted Wnt Signaling Inhibitor Sclerostin Contributes to Beige Adipogenesis in Peripheral Fat Depots.

Cells of the osteoblast lineage are increasingly identified as participants in whole-body metabolism by primarily targeting pancreatic insulin secretion or consuming energy. Osteocytes, the most abundant bone cells, secrete a Wnt-signaling inhibitor called sclerostin. Here we examined three mouse models expressing high sclerostin levels, achieved through constitutive or inducible loss of the stimulatory subunit of G-proteins (Gsα in mature osteoblasts and/or osteocytes). These mice showed progressive loss of white adipose tissue (WAT) with tendency toward increased energy expenditure but no changes in glucose or insulin metabolism. Interestingly beige adipocytes were increased extensively in both gonadal and inguinal WAT and had reduced canonical β-catenin signaling. To determine if sclerostin directly contributes to the increased beige adipogenesis, we engineered an osteocytic cell line lacking Gsα which has high sclerostin secretion. Conditioned media from these cells significantly increased expression of UCP1 in primary adipocytes, and this effect was partially reduced after depletion of sclerostin from the conditioned media. Similarly, treatment of Gsα-deficient animals with sclerostin-neutralizing antibody partially reduced the increased UCP1 expression in WAT. Moreover, direct treatment of sclerostin to wild-type mice significantly increased UCP1 expression in WAT. These results show that osteocytes and/or osteoblasts secrete factors regulating beige adipogenesis, at least in part, through the Wnt-signaling inhibitor sclerostin. Further studies are needed to assess metabolic effects of sclerostin on adipocytes and other metabolic tissues. © 2016 American Society for Bone and Mineral Research.

Abstract 68: Activation of Brown Adipose Tissue Reduces Development of Atherosclerosis

Objectives: Brown adipose tissue (BAT) recently emerged as a novel player in lipoprotein metabolism. BAT combusts high amounts fatty acids into heat resulting in reduced plasma triglyceride (TG) levels as well as obesity. However, the precise role of BAT in cholesterol metabolism and atherosclerosis development remains unclear. We aimed to assess the effect of stimulating BAT activity by ß3-adrenergic receptor (ß3-AR) agonism on lipoprotein metabolism and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism. Methods and results: Mice were fed a Western-type diet to induce dyslipidemia and were treated subcutaneously with the selective ß3-AR agonist CL316243 (3x20 μg/week) or vehicle for 10 weeks. ß3-AR agonism reduced total fat mass (-59%) and white adipose tissue (WAT) pad size (-40%). ß3-AR agonism decreased the size of intracellular lipid vacuoles in BAT, and increased UCP-1 expression in WAT, indicating activation of brown adipocytes ( i.e. BAT) as well as their precursors ( i.e. WAT). These effects were accompanied by increased uptake of glycerol tri[ 3 H]oleate from VLDL-like particles by BAT (+125%) and by WAT (+120%) as well as fatty acid oxidation (+25%) as determined by indirect calorimetry. In line with these data, activation of BAT decreased plasma levels of TG (-46%) and (V)LDL-cholesterol (-24%) and increased HDL-cholesterol (+23%), accompanied by increased reverse cholesterol transport (+2.5-fold). As a consequence of improving lipoprotein metabolism, BAT activation reduced atherosclerosis development (-43%) as well as lesion severity, indicated by more mild type I-III lesions (+64%) and reduced severe type IV-V lesions (-66%), in the aortic root. These effects were dependent on a functional hepatic apoE-LDLr clearance pathway, as BAT activation in apoe -/- and ldlr -/- mice lowered plasma TG levels but did not attenuate hypercholesterolemia and atherosclerosis Conclusion: We demonstrate that activation of BAT via the ß3-AR is a powerful tool to reduce dyslipidemia and protect against atherosclerosis. These findings indicate that activation of BAT is a promising novel strategy to combat dyslipidemia and cardiovascular disease.

Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes

Uncoupling protein (UCP)-1 expressed in brown adipose tissue plays an important role in thermogenesis. Recent data suggest that brown-like adipocytes in white adipose tissue (WAT) and skeletal muscle play a crucial role in the regulation of body weight. Understanding of the mechanism underlying the increase in UCP-1 expression level in these organs should, therefore, provide an approach to managing obesity. The thyroid hormone (TH) has profound effects on mitochondrial biogenesis and promotes the mRNA expression of UCP in skeletal muscle and brown adipose tissue. However, the action of TH on the induction of brown-like adipocytes in WAT has not been elucidated. Thus we investigate whether TH could regulate UCP-1 expression in WAT using multipotent cells isolated from human adipose tissue. In this study, triiodothyronine (T(3)) treatment induced UCP-1 expression and mitochondrial biogenesis, accompanied by the induction of the CCAAT/enhancer binding protein, peroxisome proliferator-activated receptor-γ coactivator-1α, and nuclear respiratory factor-1 in differentiated human multipotent adipose-derived stem cells. The effects of T(3) on UCP-1 induction were dependent on TH receptor-β. Moreover, T(3) treatment increased oxygen consumption rate. These findings indicate that T(3) is an active modulator, which induces energy utilization in white adipocytes through the regulation of UCP-1 expression and mitochondrial biogenesis. Our findings provide evidence that T(3) serves as a bipotential mediator of mitochondrial biogenesis.

Enhanced Leptin-Stimulated Pi3k Activation in the CNS Promotes White Adipose Tissue Transdifferentiation

The contribution of different leptin-induced signaling pathways in control of energy homeostasis is only partly understood. Here we show that selective Pten ablation in leptin-sensitive neurons (Pten(DeltaObRb)) results in enhanced Pi3k activation in these cells and reduces adiposity by increasing energy expenditure. White adipose tissue (WAT) of Pten(DeltaObRb) mice shows characteristics of brown adipose tissue (BAT), reflected by increased mitochondrial content and Ucp1 expression resulting from enhanced leptin-stimulated sympathetic nerve activity (SNA) in WAT. In contrast, leptin-deficient ob/ob-Pten(DeltaObRb) mice exhibit unaltered body weight and WAT morphology compared to ob/ob mice, pointing to a pivotal role of endogenous leptin in control of WAT transdifferentiation. Leanness of Pten(DeltaObRb) mice is accompanied by enhanced sensitivity to insulin in skeletal muscle. These data provide direct genetic evidence that leptin-stimulated Pi3k signaling in the CNS regulates energy expenditure via activation of SNA to perigonadal WAT leading to BAT-like differentiation of WAT.