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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperleptinemia is a common feature of obese women who have a higher risk of endometrial cancer than women with normal weights, and epidemiologic studies have suggested a correlation between obesity and endometrial carcinoma. Therefore, understanding of the molecular mechanism involved in leptin signaling transduction is important in endometrial cancer prevention and treatment. In this study, both isoforms of the leptin receptor (Ob-R), the long form (Ob-Rb) and short form (Ob-Ra), were detected as being expressed in six endometrial cancer cell lines with various differentiation status by western blotting, and Ob-Ra was found to be more abundant than Ob-Rb in these cells. Moreover, the expressions of both isoforms were inversely correlated with histoprognostic grading. We also showed that leptin stimulated cell proliferation and induced activations of signal transducers and activators of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK1/2), AKT, and cyclooxygenase (COX)-2 in endometrial cancer cells dose-dependently by [(3)H] thymidine incorporation assay and western blotting. Leptin-stimulation resulted in increased expression of COX-2 mRNA and prostaglandin E2 (PGE2) production of endometrial cancer cells by reverse transcription-polymerase chain reaction and enzyme immunoassay, respectively, which was effectively blocked by pharmacological inhibitors of Janus tyrosine kinase 2 (JAK2), AG490; of mitogen-activated protein kinase (MAPK) kinase, U0126; of phosphatidylinositol 3-kinase (PI3K), LY294002; and of COX-2, NS398. These results suggest that leptin promotes cell proliferation of endometrial cancer cells via the aforementioned multiple signal-transduction pathways. Leptin-induced functional activation of COX-2 is JAK2/STAT3-, MAPK/ERK-, and PI3K/AKT-dependent, indicating that COX-2 may be a critical factor of endometrial carcinogenesis in obesity.
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PMID:Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. 1915 13

Leptin, an adipocyte-derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. In this study, we found that leptin increased the migration and the expression of alphavbeta3 integrin in human chondrosarcoma cells. We also found that human chondrosarcoma tissues and chondrosarcoma cell lines had significant expression of the long form (OBRl) leptin receptor, which was higher than that in normal cartilage and human primary chondrocyte. Leptin-mediated migration and integrin upregulation were attenuated by OBRl receptor antisense oligonucleotide. Activations of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), Akt and nuclear factor-kappaB (NF-kappaB) pathways after leptin treatment were demonstrated, and leptin-induced expression of integrin and migration activity was inhibited by the specific inhibitor, small-interfering RNA and mutant of IRS-1, PI3K, Akt and NF-kappaB cascades. Taken together, our results indicated that leptin enhances the migration of chondrosarcoma cells by increasing alphavbeta3 integrin expression through the OBR1/IRS-1/PI3K/Akt/NF-kappaB signal transduction pathway.
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PMID:Leptin enhances cell migration in human chondrosarcoma cells through OBRl leptin receptor. 1916 85

In obesity, the regulatory effects of leptin, a primarily adipocyte-derived hormone, are severely disturbed affecting the control of energy homeostasis and immune functions. In addition, recent studies indicate that specific immune cells can affect glucose and lipid metabolism of liver. However, the contribution of body weight and immune cells, such as Natural Killer (NK) cells, to the regulation of the leptin-receptor expression remains elusive. Therefore, we investigated the expression of the signal-transducing long form of the leptin receptor (Ob-Rb) in diet-induced obesity and after adoptive cross-over NK cell transfer between normal weight and obese male F344 rats. Expression of Ob-Rb was significantly increased in liver in diet-induced obese rats as compared to normal weight littermates. Similarly, the expression of Ob-Rb was higher in liver of obese animals that received NK cells from either obese or normal weight donors as compared to normal weight animals that received NK cells from normal weight donors. Interestingly, normal weight animals that were transferred with NK cells from obese donors also showed a tendency towards a higher Ob-Rb expression. In contrast to the findings in liver, the expression of Ob-Rb in spleen or lung remained unaffected by changes in body weight or cross-over NK cell transfer. Our results suggest that the expression of Ob-Rb mRNA in liver, but not in spleen or lung, is dependent on the body weight but can also be influenced by NK cells, thereby indicating a bidirectional cross-talk between the metabolic and the immune system.
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PMID:Obesity and NK cells affect the expression of the long form of the leptin receptor Ob-Rb in liver of F344 rats. 1918 40

Health utilities are measures of health-related quality of life (HRQL) used in cost-effectiveness research. We evaluated whether changes in body weight were associated with changes in health utilities in the Diabetes Prevention Program (DPP) and whether associations differed by treatment assignment (lifestyle intervention, metformin, placebo) or baseline obesity severity. We constructed physical (PCS-36) and mental component summary (MCS-36) subscales and short-form-6D (SF-6D) health utility index for all DPP participants completing a baseline 36-item short form (SF-36) HRQL assessment (N = 3,064). We used linear regression to test associations between changes in body weight and changes in HRQL indicators, while adjusting for other demographic and behavioral variables. Overall differences in HRQL between treatment groups were highly statistically significant but clinically small after 1 year. In multivariable models, weight change was independently associated with change in SF-6D score (increase of 0.007 for every 5 kg weight loss; P < 0.001), but treatment effects independent of weight loss were not. We found no significant interaction between baseline obesity severity and changes in SF-6D with changes in body weight. However, increases in physical function (PCS-36) with weight loss were greater in persons with higher baseline obesity severity. In summary, improvements in HRQL are associated with weight loss but not with other effects of obesity treatments that are unrelated to weight loss. Although improvements in the SF-6D did not exceed commonly reported thresholds for a minimally important difference (0.04), these changes, if causal, could still have a significant impact on clinical cost-effectiveness estimates if sustained over multiple years.
Obesity (Silver Spring) 2009 Dec
PMID:Changes in health state utilities with changes in body mass in the Diabetes Prevention Program. 1939 May 18

Favorable health outcomes at 2 years postbariatric surgery have been reported. With exception of the Swedish Obesity Subjects (SOS) study, these studies have been surgical case series, comparison of surgery types, or surgery patients compared to subjects enrolled in planned nonsurgical intervention. This study measured gastric bypass effectiveness when compared to two separate severely obese groups not participating in designed weight-loss intervention. Three groups of severely obese subjects (N = 1,156, BMI >or= 35 kg/m(2)) were studied: gastric bypass subjects (n = 420), subjects seeking gastric bypass but did not have surgery (n = 415), and population-based subjects not seeking surgery (n = 321). Participants were studied at baseline and 2 years. Quantitative outcome measures as well as prevalence, incidence, and resolution rates of categorical health outcome variables were determined. All quantitative variables (BMI, blood pressure, lipids, diabetes-related variables, resting metabolic rate (RMR), sleep apnea, and health-related quality of life) improved significantly in the gastric bypass group compared with each comparative group (all P < 0.0001, except for diastolic blood pressure and the short form (SF-36) health survey mental component score at P < 0.01). Diabetes, dyslipidemia, and hypertension resolved much more frequently in the gastric bypass group than in the comparative groups (all P < 0.001). In the surgical group, beneficial changes of almost all quantitative variables correlated significantly with the decrease in BMI. We conclude that Roux-en-Y gastric bypass surgery when compared to severely obese groups not enrolled in planned weight-loss intervention was highly effective for weight loss, improved health-related quality of life, and resolution of major obesity-associated complications measured at 2 years.
Obesity (Silver Spring) 2010 Jan
PMID:Health outcomes of gastric bypass patients compared to nonsurgical, nonintervened severely obese. 1949 44

The increasing incidence of obesity and obesity-linked disease presents a serious global health threat. To develop truly effective therapies to modulate food intake and promote weight loss, we must understand the physiological regulators that underlie these processes. One crucial mediator of food intake and energy homeostasis is the adipose-derived hormone, leptin, which acts through neurons expressing the long form of the leptin receptor (LepRb). Although most investigation of leptin action has centered on the large population of LepRb neurons in the arcuate nucleus (ARC), this nucleus does not mediate all aspects of leptin action. Indeed, several hypothalamic and extrahypothalamic loci contain substantial numbers of LepRb neurons, each of which presumably mediates distinct aspects of leptin action, and the collective output of these various LepRb populations produces the totality of leptin function. This review will examine known central nervous system loci that contain LepRb neurons and the potential roles for discrete populations of LepRb neurons in the control of homeostatic and hedonic pathways by leptin. Understanding the unique neuroanatomical and functional roles for each locus of leptin action will be important to identify how specific aspects of food intake contribute to obesity.
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PMID:Location, location, location: the CNS sites of leptin action dictate its regulation of homeostatic and hedonic pathways. 1952 73

We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db (333)/db (333) mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y(333)Stop) and gene product that lacks STAT signaling domains. db (333)/db (333) mice have a morbidly obese phenotype, with body weights diverging from wild type as early as 4 weeks of age (P < 0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype, we performed an extensive metabolic characterization of the db (333)/db (333) mouse in relation to the well-characterized db/db mouse lacking only the long form of the leptin receptor. db (333)/db (333) mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db (333)/db (333) mice show a subtle trend toward higher body weight and insulin levels, lower oxygen, carbon dioxide production, respiratory exchange ratio (RER), and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis.
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PMID:Metabolic characterization of a mouse deficient in all known leptin receptor isoforms. 1958 70

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.
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PMID:Recent advances in understanding leptin signaling and leptin resistance. 1972 19

Leptin acts as an anorexigenic hormone in the brain, where the long form of the leptin receptor (LRb) is widely expressed in hypothalamic and extra-hypothalamic sites that are known to participate in diverse feeding circuits. The important role of leptin in energy homeostasis is demonstrated by the profound hyperphagia and morbid obesity in humans and rodents null for leptin or LRb. However, common forms of obesity are associated with high leptin levels and a failure to respond effectively to exogenous leptin; indicating a state of leptin resistance. Leptin resistance is thought to be an important component in the development of obesity. Several defects may contribute to the leptin resistant state, including a defective leptin transport across the blood-brain barrier, which reduces the availability of leptin at its receptor. Furthermore, defects in LRb signal transduction involving reduced LRb expression or the induction of feedback inhibitors have been found in leptin resistance; these defects are commonly termed cellular leptin resistance,. Finally, reduced leptin action can result in the disruption of proper neuronal interactions, by altering neuronal wiring. Interestingly, some leptin functions remain intact in the leptin-resistant state, such as cardiovascular leptin effects. The appearance of selective leptin resistance is mirrored by the observation that cellular leptin resistance has been found only in some subpopulations of hypothalamic LRb neurons. Current efforts to dissect leptin function in specific populations of LRb neurons will increase our understanding of these complexities of leptin physiology.
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PMID:Leptin-signaling pathways and leptin resistance. 1995 80

Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.
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PMID:Signaling through Tyr985 of leptin receptor as an age/diet-dependent switch in the regulation of energy balance. 2008 94


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