Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activin-betaA and activin-betaB (encoded by Inhba and Inhbb genes, respectively) are closely related TGF-beta superfamily members that participate in a variety of biological processes. We previously generated mice with an insertion allele at the Inhba locus, Inhba(BK). In this allele, the sequence encoding the Inhba mature domain is replaced with that of Inhbb, rendering the gene product functionally hypomorphic. Homozygous (Inhba(BK/BK)) and hemizygous (Inhba(BK/-)) mice are smaller and leaner than their wild-type littermates, and many tissues are disproportionately small relative to total body weight. To determine the mechanisms that contribute to these phenomena, we investigated the metabolic consequences of the mutation. Although the growth of Inhba(BK) mice is improved by providing a calorie-rich diet, diet-induced obesity, fatty liver, and insulin resistance (hallmarks of chronic caloric excess) do not develop, despite greater caloric intake than wild-type controls. Physiological, molecular, and biochemical analyses all revealed characteristics that are commonly associated with increased mitochondrial energy metabolism, with a corresponding up-regulation of several genes that reflect enhanced mitochondrial biogenesis and function. Oxygen consumption, an indirect measure of the metabolic rate, was markedly increased in Inhba(BK/BK) mice, and polarographic analysis of liver mitochondria revealed an increase in ADP-independent oxygen consumption, consistent with constitutive uncoupling of the inner mitochondrial membrane. These findings establish a functional relationship between activin signaling and mitochondrial energy metabolism and further support the rationale to target this signaling pathway for the medical treatment of cachexia, obesity, and diabetes.
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PMID:Activin signaling: effects on body composition and mitochondrial energy metabolism. 1938 32

Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins that may uncouple the transport of protons across the inner mitochondrial membrane from electron transport and the synthesis of ATP from ADP, hence generating heat rather than energy. In mammals, more than five family members have been identified, including UCP1, UCP2, UCP3, UCP4 (or BMCP1/UCP5) and UCP5. The UCPs may play an important role in energy homeostasis and have become prominent in the fields of thermogenesis, obesity, diabetes and free-radical biology and have been considered candidate genes for obesity and insulin resistance. They have been as important potential targets for treatment of aging, degenerative diseases, diabetes and obesity. Recently, a series of studies showed the polymorphisms of UCPs gene association with the fat metabolism, obesity and diabetes. This review summarizes data supporting the roles of UCP2 and UCP3 in energy dissipation, as well as the genetic variety association with fat metabolism, obesity and diabetes in humans.
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PMID:The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes. 1941 8

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (Vo(2)). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak Vo(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.
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PMID:Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice. 1961 6

TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6alpha-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion in vivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.
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PMID:TGR5-mediated bile acid sensing controls glucose homeostasis. 2039 10

Central obesity shows impaired platelet responses to the antiaggregating effects of nitric oxide (NO), prostacyclin, and their effectors--guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). The influence of weight loss on these alterations is not known. To evaluate whether a diet-induced body-weight reduction restores platelet sensitivity to the physiological antiaggregating agents and reduces platelet activation in subjects affected by central obesity, we studied 20 centrally obese subjects before and after a 6-month diet intervention aiming at reducing body weight by 10%, by measuring (i) insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA(IR))); (ii) plasma lipids; (iii) circulating markers of inflammation of adipose tissue and endothelial dysfunction, and of platelet activation (i.e., soluble CD-40 ligand (sCD-40L) and soluble P-selectin (sP-selectin)); (iv) ability of the NO donor sodium nitroprusside (SNP), the prostacyclin analog Iloprost and the cyclic nucleotide analogs 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) to reduce platelet aggregation in response to adenosine-5-diphosphate (ADP); and (v) ability of SNP and Iloprost to increase cGMP and cAMP. The 10 subjects who reached the body-weight target showed significant reductions of insulin resistance, adipose tissue, endothelial dysfunction, and platelet activation, and a significant increase of the ability of SNP, Iloprost, 8-Br-cGMP, and 8-Br-cAMP to reduce ADP-induced platelet aggregation and of the ability of SNP and Iloprost to increase cyclic nucleotide concentrations. No change was observed in the 10 subjects who did not reach the body-weight target. Changes of platelet function correlated with changes of HOMA(IR). Thus, in central obesity, diet-induced weight loss reduces platelet activation and restores the sensitivity to the physiological antiaggregating agents, with a correlation with improvements in insulin sensitivity.
Obesity (Silver Spring) 2010 Apr
PMID:In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin. 1983 74

It is a desirable goal to stimulate fuel oxidation in adipocytes and shift the balance toward less fuel storage and more burning. To understand this regulatory process, respiration was measured in primary rat adipocytes, mitochondria, and fat-fed mice. Maximum O(2) consumption, in vitro, was determined with a chemical uncoupler of oxidative phosphorylation (carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)). The adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio was measured by luminescence. Mitochondria were localized by confocal microscopy with MitoTracker Green and their membrane potential (Delta psi(M)) measured using tetramethylrhodamine ethyl ester perchlorate (TMRE). The effect of N-acetylcysteine (NAC) on respiration and body composition in vivo was assessed in mice. Addition of FCCP collapsed Delta psi(M) and decreased the ATP/ADP ratio. However, we demonstrated the same rate of adipocyte O(2) consumption in the absence or presence of fuels and FCCP. Respiration was only stimulated when reactive oxygen species (ROS) were scavenged by pyruvate or NAC: other fuels or fuel combinations had little effect. Importantly, the ROS scavenging role of pyruvate was not affected by rotenone, an inhibitor of mitochondrial complex I. In addition, mice that consumed NAC exhibited increased O(2) consumption and decreased body fat in vivo. These studies suggest for the first time that adipocyte O(2) consumption may be inhibited by ROS, because pyruvate and NAC stimulated respiration. ROS inhibition of O(2) consumption may explain the difficulty to identify effective strategies to increase fat burning in adipocytes. Stimulating fuel oxidation in adipocytes by decreasing ROS may provide a novel means to shift the balance from fuel storage to fuel burning.
Obesity (Silver Spring) 2010 Aug
PMID:Respiration in adipocytes is inhibited by reactive oxygen species. 2003 77

Prohibitin is a multifunctional protein participating in a plethora of essential cellular functions, such as cell signaling, apoptosis, survival and proliferation. In the liver, deficient prohibitin activity participates in the progression of non-alcoholic steatohepatitis and obesity, according to mechanisms that still must be elucidated. In this study, we have used a combination of transcriptomics and proteomics technologies to investigate the response of human hepatoma PLC/PRF/5 cells to prohibitin silencing to define in detail the biological function of hepatic Phb1 and to elucidate potential prohibitin-dependent mechanisms participating in the maintenance of the transformed phenotype. Abrogation of prohibitin reduced proliferation and induced apoptosis in human hepatoma cells in a mechanism dependent on NF kappaB signaling. Moreover, down-regulation of ERp29 together with down-regulation of Erlin 2 suggests ER stress. In agreement, increased C/EBP homologous protein levels, poly-ADP ribose polymerase cleavage and activation of caspase 12 and downstream caspase 7 evidenced ER stress-induced apoptosis. Down-regulation of proteasome activator complex subunit 2 and stathmin as well as accumulation of ubiquitinated proteins suggest interplay between ER stress and proteasome malfunction. Taken together, our results provide evidences for prohibitin having a central role in the maintenance of the transformed and invasive phenotype of human hepatoma cells and may further support previous studies suggesting prohibitin as a potential clinical target.
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PMID:Prohibitin deficiency blocks proliferation and induces apoptosis in human hepatoma cells: molecular mechanisms and functional implications. 2018 55

Dietary restriction (DR) delays or prevents age-related diseases and extends lifespan in species ranging from yeast to primates. Although the applicability of this regimen to humans remains uncertain, a proportional response would add more healthy years to the average life than even a cure for cancer or heart disease. Because it is unlikely that many would be willing or able to maintain a DR lifestyle, there has been intense interest in mimicking its beneficial effects on health, and potentially longevity, with drugs. To date, such efforts have been hindered primarily by our lack of mechanistic understanding of how DR works. Sirtuins, NAD(+)-dependent deacetylases and ADP-ribosyltransferases that influence lifespan in lower organisms, have been proposed to be key mediators of DR, and based on this model, the sirtuin activator resveratrol has been proposed as a candidate DR mimetic. Indeed, resveratrol extends lifespan in yeast, worms, flies, and a short-lived species of fish. In rodents, resveratrol improves health, and prevents the early mortality associated with obesity, but its precise mechanism of action remains a subject of debate, and extension of normal lifespan has not been observed. This review summarizes recent work on resveratrol, sirtuins, and their potential to mimic beneficial effects of DR.
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PMID:Resveratrol, sirtuins, and the promise of a DR mimetic. 2021 19

Poly (ADP-ribose) polymerase-1 (PARP1) regulates gene expression as a transcriptional cofactor and protein functions via poly (ADP-ribosyl)ation. This study was aimed to determine the effect of Parp1 gene deficiency on diet-induced obesity and energy metabolism. Parp1-knockout (Parp-KO) and wild-type (WT) mice on the same genetic background were fed either normal chow or high-fat (HF) diet. Food intake and weight gain were monitored weekly. Plasma levels of glucose, leptin, and insulin were monitored monthly. At 19 weeks, locomotor activity, body composition, respiratory quotient and heat production, glucose and insulin tolerance, and fat reabsorption were analyzed. Parp-KO mice are highly susceptible to diet-induced obesity, accumulation of fat tissue, and they develop hyperleptinemia and insulin resistance and glucose intolerance compared with their WT counterparts. The increased weight gain is due to decreased metabolic rate, heat production, and total energy expenditure (EE). Paradoxically, food intake is less, and the motor activity and oxidation of fat are higher in Parp-KO mice. Absorption of fatty acids is not altered between the groups after HF diet. These results suggest that malfunction of PARP1 signaling exacerbates diet-induced obesity, hyperleptinemia, and insulin resistance, and that it decreases EE in 129 mice.
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PMID:PARP1 deficiency exacerbates diet-induced obesity in mice. 2033 98

Insufficient platelet function suppression by aspirin is a predictor of cardiovascular events in high-risk patients. The authors assessed the impact of obesity on platelet responsiveness before and after 2 weeks of aspirin 81 mg/d in 2014 people. Obese individuals had greater baseline platelet reactivity. Comparing obese and nonobese individuals after aspirin therapy, results for aggregometry to collagen were 6.7 vs 6.1 ohms, P=.008; aggregometry to adenosine diphosphate were 13.1 vs 11.8 ohms,P<.0001; aggregometry to arachidonic acid (AA) were 4.9% vs 8.3% nonzero aggregation, P=.002; urinary excretion of 11-dehydro-thromboxane B2 (Tx-M) were 4.9% vs 8.3% nonzero aggregation, P=.002; and aspirin resistance were 26.% vs 20.5%, P=.002; respectively. These remained significantly different for AA aggregation and Tx-M excretion after adjustment for covariates. Obese individuals have greater native platelet reactivity and retain greater reactivity after suppression by aspirin.
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PMID:Effect of obesity on platelet reactivity and response to low-dose aspirin. 2037 6


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