Abstract:We have identified a novel cDNA encoding a protein highly homologous to the mammalian brown fat uncoupling protein (UCP). Unlike the known UCP, which is expressed specifically in brown adipose tissue, the UCP homolog (UCPH) mRNA is expressed in a variety of tissues, with predominant expression in human white adipose tissue and skeletal muscle. In the white adipose tissue of ob/ob and db/db mice, the UCPH transcript is induced approximately fivefold relative to lean littermate controls. Expression of murine UCP… Show more
“…7). These results are consistent with reports that UCP2 expression in WAT is five-fold higher in leptin-deficient ob/ob mice and leptin-resistant db/db mice than in respective littermate controls [46] and correlates with obesity in humans [47]. Fig.…”
BackgroundObesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation.ResultsWe found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage.ConclusionsLeptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-017-0135-y) contains supplementary material, which is available to authorized users.
“…7). These results are consistent with reports that UCP2 expression in WAT is five-fold higher in leptin-deficient ob/ob mice and leptin-resistant db/db mice than in respective littermate controls [46] and correlates with obesity in humans [47]. Fig.…”
BackgroundObesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation.ResultsWe found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage.ConclusionsLeptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-017-0135-y) contains supplementary material, which is available to authorized users.
“…UCPs are mitochondrial inner membrane proteins that uncouple oxidative respiration, and three such proteins have been reported thus far [19]. UCP1 is mainly expressed in BAT [20,21], UCP2 is ubiquitously expressed in various tissues in the body [22,23], and UCP3 is specific for skeletal muscle and BAT [24]. PRDM16 is a dominant regulator of brown fat development, and reduction in its expression has been associated with a decrease in the expression of UCP1 [25].…”
Background: Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea and has been considered a natural agent that can help to reduce the risk of obesity.Objective: The aim of this study was to investigate the effects of EGCG on thermogenesis and mitochondrial biogenesis in brown adipose tissue (BAT) of diet-induced obese mice.Methods: Male C57BL/6J mice were provided a high-fat diet for 8 weeks to induce obesity, following which they were divided into two groups: one on a high-fat control diet and the other on a 0.2% EGCG (w/w)-supplemented high-fat diet for another 8 weeks.Results: The EGCG-supplemented group showed decreased body weight gain, and plasma and liver lipids. EGCG-fed mice exhibited higher body temperature and mitochondrial DNA (mtDNA) content in BAT. The messenger RNA levels of genes related to thermogenesis and mitochondrial biogenesis in BAT were increased by EGCG. Moreover, adenosine monophosphate-activated protein kinase (AMPK) activity in BAT was stimulated by EGCG.Conclusions: The results suggest that EGCG may have anti-obesity properties through BAT thermogenesis and mitochondria biogenesis, which are partially associated with the regulation of genes related to thermogenesis and mitochondria biogenesis, and the increase in mtDNA replication and AMPK activation in BAT of diet-induced obese mice.
“…UCP2 and UCP3 (UCP2/3) are two of the five homologs of UCP1, the first UCP protein demonstrated to have a mitochondrial uncoupling function (Gimeno et al 1997; Matthias et al 2000). UCP2/3 share 57-59% amino-acid sequence identity with UCP1 (Krauss et al 2005).…”
Energy expenditure decreases with age, but in the oldest-old, energy demand for maintenance of body functions increases with declining health. Uncoupling proteins have profound impact on mitochondrial metabolic processes; therefore, we focused attention on mitochondrial uncoupling protein genes. Alongside resting metabolic rate (RMR), two SNPs in the promoter region of UCP2 were associated with healthy aging. These SNPs mark potential binding sites for several transcription factors; thus, they may affect expression of the gene. A third SNP in the 3′-UTR of UCP3 interacted with RMR. This UCP3 SNP is known to impact UCP3 expression in tissue culture cells, and it has been associated with body weight and mitochondrial energy metabolism. The significant main effects of the UCP2 SNPs and the interaction effect of the UCP3 SNP were also observed after controlling for fat-free mass (FFM) and physical-activity related energy consumption. The association of UCP2/3 with healthy aging was not found in males. Thus, our study provides evidence that the genetic risk factors for healthy aging differ in males and females, as expected from the differences in the phenotypes associated with healthy aging between the two sexes. It also has implications for how mitochondrial function changes during aging.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
