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)

An autosomal genomic scan to search for linkage to obesity and energy metabolism was completed in Pima Indians, a population prone to obesity. Obesity was assessed by percent body fat (by hydrodensitometry) and fat distribution (the ratio of waist circumference to thigh circumference). Energy metabolism was measured in a respiratory chamber as 24-h metabolic rate, sleeping metabolic rate, and 24-h respiratory quotient (24RQ), an indicator of the ratio of carbohydrate oxidation to fat oxidation. Five hundred sixteen microsatellite markers with a median spacing of 6.4 cM were analyzed, in 362 siblings who had measurements of body composition and in 220 siblings who had measurements of energy metabolism. These comprised 451 sib pairs in 127 nuclear families, for linkage analysis to obesity, and 236 sib pairs in 82 nuclear families, for linkage analysis to energy metabolism. Pointwise and multipoint methods for regression of sib-pair differences in identity by descent, as well as a sibling-based variance-components method, were used to detect linkage. LOD scores >=2 were found at 11q21-q22, for percent body fat (LOD=2.1; P=.001), at 11q23-q24, for 24-h energy expenditure (LOD=2.0; P=.001), and at 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0; P=.0001), for 24RQ, by pointwise and multipoint analyses. With the variance-components method, the highest LOD score (LOD=2.3 P=.0006) was found at 18q21, for percent body fat, and at 1p31-p21 (LOD=2.8; P=.0003), for 24RQ. Possible candidate genes include LEPR (leptin receptor), at 1p31, and ASIP (agouti-signaling protein), at 20q11.2.
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PMID:Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. 949 55

Leptin has been hypothesized to be a pathophysiologic link between obesity and cardiovascular diseases. Because the adenylate cyclase (AC) system is a main effector of beta-adrenergic receptors and leptin has been shown to modulate AC activity in other cell lines, a leptin impact on cardiac AC activity was hypothesized. Therefore, acute and chronic effects of leptin on a rat cardiac cell line (H9c2) were investigated. Leptin affected both basal (+ 13% at 30 min and -16.4% after 18 h v untreated cells) and catecholamine-stimulated AC activity (isoproterenol + leptin at 30 min or 18 h was +21% v untreated cells; norepinephrine + leptin at 30 min was +38.8% v untreated cells; and norepinephrine + leptin at 18 h was +6% v untreated cells). Thus, long-term leptin treatment was associated with a reduced AC activity and a different responsiveness to catecholamines. The AC activity on leptin treatment was accompanied by changes in levels of proteins structurally or functionally related to AC complex (AC, Gas, Gai, p21-ras). These data indicate that the AC complex is profoundly affected at more than one level by leptin treatment in the H9c2 cardiac cell line. Differences in AC activity after short- and long-term exposure to leptin and the interaction between leptin and catecholamine might provide further insight to the understanding of the development of hypertension and congestive heart failure in obese patients.
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PMID:Leptin affects adenylate cyclase activity in H9c2 cardiac cell line: effects of short- and long-term exposure. 1211 13

Obesity is a major health problem in industrialized societies, and fatty liver disease (hepatic steatosis) is common in obese individuals. Oxidative stress originating from increased intracellular levels of fatty acids has been implicated as a cause of hepatocellular injury in steatosis, although the precise mechanisms remain to be elucidated. p53, widely known as a tumor suppressor, has been shown often to be activated in stressed cells, inducing cell cycle arrest or death. Here we demonstrate that p53 is involved in the molecular mechanisms of hepatocellular injury associated with steatosis. We found that p53 in the nucleus is induced in the liver from two mouse models of fatty liver disease, ob/ob and a transgenic mouse model that overexpresses an active form of sterol regulatory element-binding protein-1 in the liver (TgSREBP-1), the one with obesity and the other without obesity. This activation of the p53 pathway leads to the elevation of p21 mRNA expression, which can be considered an indicator of p53 activity, because ob/ob mice lacking p53 generated by targeting gene disruption exhibited the complete restoration of the p21 elevation to wild type levels. Consistent with these results, the amelioration of hepatic steatosis caused by Srebp-1 gene disruption in ob/ob mice lowered the p21 expression in a triglyceride content-dependent manner. Moreover, p53 deficiency in ob/ob mice resulted in a marked improvement of plasma alanine aminotransferase levels, demonstrating that p53 is involved in the mechanisms of hepatocellular injury. In conclusion, we revealed that p53 plays an important role in the pathogenesis of fatty liver disease.
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PMID:p53 involvement in the pathogenesis of fatty liver disease. 1498 41

Apolipoprotein M (apoM) is a 26-kDa protein that is mainly associated with high-density lipoprotein (HDL) in human plasma, with a small proportion present in triglyceride-rich lipoproteins (TGRLP) and low-density lipoproteins (LDL). Human apoM gene is located in p21.31 on chromosome 6 (chromosome 17, in mouse). Human apoM cDNA (734 base pairs) encodes 188-amino acid residue-long protein. It belongs to lipocalin protein superfamily. Human tissue expression array study indicates that apoM is only expressed in liver and in kidney and small amounts are found in fetal liver and kidney. In situ apoM mRNA hybridization demonstrates that apoM is exclusively expressed in the hepatocytes and in the tubule epithelial cells in kidney. Expression of apoM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF) and leptin in vivo and/or in vitro. It has been demonstrated that apoM expression is dramatically decreased in apoA-I deficient mouse. Hepatocyte nuclear factor-1alpha (HNF-1alpha) is an activator of apoM gene promoter. Deficiency of HNF-1alpha mouse shows lack of apoM expression. Mutations in HNF-1alpha (MODY3) have reduced serum apoM levels. Expression of apoM is significantly decreased in leptin deficient (ob/ob) mouse or leptin receptor deficient (db/db) mouse. ApoM concentration in plasma is positively correlated to leptin level in obese subjects. These may suggest that apoM is related to the initiation and progression of MODY3 and/or obesity.
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PMID:Apolipoprotein M. 1546 12

Adipocyte hyperplasia is characteristic of some forms of human obesity, but the role of adipocyte number in obesity and how normal adipocyte number is established are unclear. Preadipocytes proliferate and then differentiate to become mitotically quiescent adipocytes. This involves exit from the cell cycle, a process regulated by cell cycle inhibitors such as the cyclin-dependent kinase inhibitors (CDKIs) p27 and p21. 3T3-L1 preadipocytes show marked changes in p27 and p21 during differentiation, suggesting CDKIs may regulate establishment of adipocyte number in vivo. To study the role of these CDKIs in adipogenesis, we analyzed adult p27 knockout (p27KO), p21 knockout (p21KO), p27/p21 double knockout (DBKO), and wild-type (WT) mice. Adult DBKO mice weighed 100% more and had fourfold increases in body fat percentage compared with WT. Fat pad weights were increased 80, 90, and 500% in p27KO, p21KO, and DBKO mice, respectively, compared with WT. Adipocyte numbers of p27KO, p21KO, and DBKO mice were 1.9-, 1.7-, and 6.1-fold, respectively, that of WT; adipocyte size was not increased. DBKO mice showed glucose intolerance, insulin insensitivity, hepatic steatosis and dyslipidemia; gradations of these effects occurred in p27KO and p21KO mice. In conclusion, p27KO and p21KO mice are obese because of adipocyte hyperplasia, and DBKO mice have further increases in obesity and adipocyte hyperplasia, indicating that their functions in establishing adipocyte number are not redundant. p27 and p21 are major regulators of adipocyte number in vivo, and knockouts lacking one or both of these proteins provide models for producing adipocyte hyperplasia and understanding its metabolic consequences.
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PMID:Loss of cyclin-dependent kinase inhibitors produces adipocyte hyperplasia and obesity. 1546 64

Green tea catechins, especially (-)-epigallocatechin gallate (EGCG), have been proposed as a chemopreventative for obesity, diabetes, cancer, and cardiovascular diseases. However, relatively little is known about the mechanism of the action of EGCG on fat cell function. This study was designed to investigate the pathways of EGCG's modulation of the mitogenesis of 3T3-L1 preadipocytes. Preadipocyte proliferation as indicated by an increased number of cells and greater incorporation of bromodeoxyuridine (BrdU) was inhibited by EGCG in dose-, time-, and growth phase-dependent manners. Also, EGCG dose and time dependently decreased levels of phospho-ERK1/2, Cdk2, and cyclin D(1) proteins, reduced Cdk2 activity, and increased levels of G(0)/G(1) growth arrest, p21(waf/cip), and p27(kip1), but not p18(ink), proteins and their associations to Cdk2. However, neither MEK1, ERK1/2, p38 MAPK, phospho-p38, JNK, nor phospho-JNK was changed. Increased phospho-ERK1/2 content and Cdk2 activity, respectively, via the transfection of MEK1 and Cdk2 cDNA into preadipocytes prevented EGCG from reducing cell numbers. These data demonstrate the ERK- and Cdk2-dependent antimitogenic effects of EGCG. Moreover, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in changing the mitogenic signals. The signal of EGCG in reducing growth of 3T3-L1 preadipocytes differed from that of 3T3 fibroblasts. Results of this study may relate to the mechanism by which EGCG modulates body weight.
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PMID:Antimitogenic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the ERK and Cdk2 pathways. 1564 88

Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.
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PMID:Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. 1675 79

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

Leptin-deficient ob/ob mice are a murine model for obesity, insulin resistance, and diabetes. Here we report that non-lethal abdominal irradiation (a single fraction of 850 cGy) to ob/ob mice retarded rapid gain of body weight, leading to amelioration of obesity without marked changes in food intake. This effect was observed only in ob/ob mice and not in lean controls. Reduction of body weight was accompanied by decreased adipose tissue weight without any marked change in the size of adipocytes, indicating prevention of hyperplasia rather than hypertrophy. Gene expression of the radiation-inducible cdk-inhibitor, p21, and the adipocytokines, tumor necrosis factor alpha and interleukin-1beta, were induced as expected; but genes involved in adipogenesis such as peroxisome proliferator-activated receptor gamma and adipsin were not affected in the irradiated adipose tissue. Inversely, hepatic lipid content was elevated with concomitant increases in the expression of lipogenic enzymes such as fatty acid synthase (FAS), and sterol regulatory element-binding protein 1c. Despite the decreased adiposity, there was no improvement in hyperglycemia and hyperinsulinemia after the irradiation. In conclusion, abdominal irradiation to ob/ob mice affected the progression of obesity and altered the energy metabolism between organs through a novel mechanism, implicating a new approach or factor for understanding and treatment of obesity.
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PMID:Abdominal Irradiation Ameliorates Obesity in ob/ob Mice. 1818 14

Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21(WAF1/CIP1), a cyclin-dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this process is unknown. Using both in vitro and in vivo systems, we show that p21 is crucial for maintaining adipocyte hypertrophy and obesity-induced insulin resistance. The absence of p21 in 3T3-L1 fibroblasts by RNA-mediated interference knockdown or in embryonic fibroblasts from p21(-/-) mice impaired adipocyte differentiation, resulting in smaller adipocytes. Despite normal adipose tissue mass on a normal diet, p21(-/-) mice fed high energy diets had reduced adipose tissue mass and adipocyte size accompanied by a marked improvement in insulin sensitivity. Knockdown of p21 in enlarged epididymal fat of diet-induced obese mice and also in fully differentiated 3T3-L1 adipocytes caused vigorous apoptosis by activating p53. Thus, p21 is involved in both adipocyte differentiation and in protecting hypertrophied adipocytes against apoptosis. Via both of these mechanisms, p21 promotes adipose tissue expansion during high fat diet feeding, leading to increased downstream pathophysiological consequences such as insulin resistance.
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PMID:Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance. 1844 90


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