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)

Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty. In high fat-fed rodents, the timing of vaginal opening (VO) is advanced, suggesting that puberty begins earlier. Because obesity can increase androgens, which interfere with normal steroid feedback in adult females, we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat-fed mice. Age at VO was examined in mice fed high-fat or low-fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle (controls). VO was advanced in high-fat vs. low-fat controls, and flutamide blocked this advancement. VO was also delayed in low fat-fed flutamide-treated females, suggesting involvement of androgens in the timing of normal puberty. We next investigated if high-fat diet-induced insulin resistance contributes to early VO, as elevated insulin can stimulate androgen production. VO was examined in mice on either diet treated with the insulin sensitizer metformin. Metformin blocked high-fat advancement of VO but did not alter the timing of VO in low fat-fed mice. Insulin was elevated in high fat-fed females that had undergone VO compared with age-matched low fat-fed or metformin-treated animals on either diet that had not undergone VO. Together, these data suggest a model in which metabolic changes induced by high-fat diet, including transient increased circulating insulin, act in part by increasing androgen action to influence the timing of puberty in females.
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PMID:Androgen receptor antagonism and an insulin sensitizer block the advancement of vaginal opening by high-fat diet in mice. 1960 81

Hyperglycaemia is a typical feature of metabolic syndrome (MeTS) and one of its independent diagnostic criteria. The term includes impaired glucose homeostasis (impaired fasting glucose and impaired glucose tolerance) and type 2 diabetes mellitus. Although glycaemic control has been shown to lower the risk of microvascular events, the effect of intensive glycaemic control on macrovascular outcomes is less clear. Epidemiological studies show hyperglycaemia, particularly the postprandial one, to be a clear risk factor for cardiovascular (CV) mortality and morbidity. However, the intervention studies are less conclusive. The large interventional studies published in 2008 and 2009 (UKPDS, VADT, ACCORD, ADVANCE, RECORD) advocate the controlling of nonglycemic risk factors (through blood pressure control, lipid lowering with statin therapy, aspirin therapy, and lifestyle modifications) as the primary strategies for reducing the burden of CV disease in people with diabetes, and demonstrated the need for individualized approach to the patients' care in terms of blood glucose control. The patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap CV benefit from intensive glycemic control. Conversely, it is possible that potential risks of intensive glycaemic control (hypoglycaemia) may outweigh its benefits in other patients, such as those with a very long duration ofdiabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. According to the latest recommendations of the Czech Diabetes Society that are in line with the European and US standards the best way to protect type 2 diabetic patients against coronary and cerebrovascular disease is to target all cardiovascular risk factors (blood pressure treatment, including lipid-lowering with statins, aspirin prophylaxis, smoking cessation, and healthy lifestyle behaviors hypertension, dyslipidemia, obesity and other symptoms of metabolic syndrome. The target HbA1c levels in patients with the low CV risk shoul be below 4.5%. Less strict goals (HbA1c below 6%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions or those with long-standing diabetes. The individual targets should be achieved safely (without hypoglycaemias). Slow advancing in diabetes compensation is preferred. Lifestyle changes are the cornerstone of therapy. Metformin is the drug of choice; its administration, together with lifestyle changes, should be initiated immediately after the diagnoses of diabetes. If monotherapy does not provide satisfactory glucose control, other oral antidiabetic agents or insulin are added to the combination. Since it is not known which hypoglycaemic agents are beneficial from the perspective of long-term patient prognosis, the selection is liberal. Contraindication of the various farmaceuticals must be respected. It is possible to use a range of different combinations, metformin is administered with a glitazone (zero risk of hypoglycaemias is the advantage) with sulphonylurea derivatives (low price is the advantage) with glinides, with incretins, acarbose, antiobesity agents or insulin. The next step is a triple combination of hypoglycaemic agents with different mechanisms of action. Therapy also includes education focusing on changes to dietary and lifestyle habits, including smoking cessation, and education related to the prevention of complications, with particular regard to prevention of diabetic foot and atherosclerosis.
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PMID:[Treatment of diabetes in metabolic syndrome]. 1973 68

The excessive supply of fatty acids to the liver contributes to hepatic insulin resistance and endoplasmic reticulum (ER) stress associated with obesity or type 2 diabetes mellitus. Furthermore, excess and/or prolonged ER stress contributes to hepatic cell death deteriorating nonalcoholic fatty liver disease to steatohepatitis. The aim of this study was to investigate the effects of metformin on palmitate-induced ER stress and hepatic insulin resistance in HepG2 cells. Metformin significantly inhibited palmitate-induced cell death and apoptosis via caspase-3 activation. Metformin also blocked the induction of ER stress proteins (GRP78, Chop, Cleaved ATF-6, p-eIF2 alpha and XBP-1) and regulated serine phosphorylation of IRS-1. Metformin may therefore protect hepatocytes from death induced by saturated fatty acids. These data may also provide a further rationale for exploring the use of metformin in the treatment of non-alcoholic fatty liver disease, revealing its blocking effect for hepatic insulin resistance evoked by saturated fatty acids.
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PMID:Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells. 2003 65

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women and the most common cause of anovulatory infertility, affecting 5-10% of the population. Approximately 60-70% of PCOS patients are obese. Although it is well known that obesity is associated with insulin resistance, most studies have shown that impaired insulin sensitivity is present without obesity. Hyper-insulinemia associated with insulin resistance has been causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism and metabolic disturbances. PCOS patients often have an atherogenic lipid profile and increased incidence of cardiovascular risk factors and type 2 diabetes. It has been demonstrated that by reducing hyper-insulinemia, insulin-lowering agents might improve endocrine and reproductive abnormalities in PCOS patients, and have numerous beneficial effects on multiple cardiovascular risk factors in PCOS. Metformin is currently the preferred insulin-sensitizing drug for chronic treatment of PCOS and has been shown to improve the metabolic profile, menstrual cyclicity and fertility in women with PCOS, and is associated with weight loss. In this review the metabolic comorbidities of PCOS and their therapeutic options are discussed.
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PMID:Polycystic ovary syndrome and metabolic comorbidities: therapeutic options. 2006 40

The molecular mechanisms responsible for the association of obesity with adverse colon cancer outcomes are poorly understood. We investigated the effects of a high-energy diet on growth of an in vivo colon cancer model. Seventeen days following the injection of 5x10(5) MC38 colon carcinoma cells, tumors from mice on the high-energy diet were approximately twice the volume of those of mice on the control diet. These findings were correlated with the observation that the high-energy diet led to elevated insulin levels, phosphorylated AKT, and increased expression of fatty acid synthase (FASN) by the tumor cells. Metformin, an antidiabetic drug, leads to the activation of AMPK and is currently under investigation for its antineoplastic activity. We observed that metformin blocked the effect of the high-energy diet on tumor growth, reduced insulin levels, and attenuated the effect of diet on phosphorylation of AKT and expression of FASN. Furthermore, the administration of metformin led to the activation of AMPK, the inhibitory phosphorylation of acetyl-CoA carboxylase, the upregulation of BNIP3 and increased apoptosis as estimated by poly (ADP-ribose) polymerase (PARP) cleavage. Prior work showed that activating mutations of PI3K are associated with increased AKT activation and adverse outcome in colon cancer; our results demonstrate that the aggressive tumor behavior associated with a high-energy diet has similar effects on this signaling pathway. Furthermore, metformin is demonstrated to reverse the effects of the high-energy diet, thus suggesting a potential role for this agent in the management of a metabolically defined subset of colon cancers.
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PMID:Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. 2022 37

Metformin demonstrates anorectic effects in vivo and inhibits neuropeptide Y expression in cultured hypothalamic neurons. Here we investigated the mechanisms implicated in the modulation of feeding by metformin in animals rendered obese by long-term high-fat diet (diet-induced obesity [DIO]) and in animals resistant to obesity (diet resistant [DR]). Male Long-Evans rats were kept on normal chow feeding (controls) or on high-fat diet (DIO, DR) for 6 months. Afterward, rats were treated 14 days with metformin (75 mg/kg) or isotonic sodium chloride solution and killed. Energy efficiency, metabolic parameters, and gene expression were analyzed at the end of the high-fat diet period and after 14 days of metformin treatment. At the end of the high-fat diet period, despite higher leptin levels, DIO rats had higher levels of hypothalamic neuropeptide Y expression than DR or control rats, suggesting a central leptin resistance. In DIO but also in DR rats, metformin treatment induced significant reductions of food intake accompanied by decreases in body weight. Interestingly, the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus. These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin. Thus, they provide a rationale for novel therapeutic approaches associating leptin and metformin in the treatment of obesity.
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PMID:The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. 2030 24

Obesity is fast becoming a bane for the present civilization, as a result of sedentary lifestyle, atherogenic diet, and a susceptible thrifty genotype. The concept of metabolic syndrome, which is a constellation of metabolic disturbances, has crystallized over the last 80 years with the aim of identifying those at greater risk of developing type 2 diabetes and cardiovascular disease. These patients have visceral obesity and insulin resistance characterized by hypertyriglyceridemia. Recently, it has been realized that they are also at an increased risk of chronic renal disease. Release of adipocytokines leads to endothelial dysfunction. There is also activation of systemic and local renin-angiotensin-aldosterone system, oxidative stress, and impaired fibrinolysis. This leads to glomerular hyperfiltration, proteinuria, focal segmental glomerulosclerosis (FSGS), and ultimately end-stage renal disease (ESRD). Treatment consists of lifestyle modifications along with optimal control of blood pressure, blood sugar and lipids. Metformin and thiazolidenidiones reduce insulin resistance; while angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria and have a renoprotective effect. Exciting new medical therapies on the horizon include rimonabant a cannabinoid receptor type 1 antagonist, soy proteins, and peroxisome proliferator-activated receptor (PPAR) agonist. Bariatric surgery for morbid obesity has also been shown to be effective in treating metabolic syndrome.
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PMID:Metabolic syndrome and chronic kidney disease. 2036 11

To evaluate the effect of metformin on basal and insulin-induced glucose uptake in subcutaneous and visceral preadipocyte-derived adipocytes from obese and non-obese patients, preadipocytes were obtained from subcutaneous and visceral fat depots during abdominal surgery. Differentiation efficiency was evaluated by measurement of intracellular triglyceride accumulation. Preadipocyte-derived adipocytes were treated with metformin (1 mM) for 24 h with or without the addition of insulin (100 nM) for 20 min and glucose uptake was measured. In cells from each donor, intracellular triglyceride accumulation was more abundant in subcutaneous preadipocyte-derived adipocytes than in visceral preadipocyte-derived adipocytes (p < 0.001). Insulin stimulated glucose uptake in subcutaneous preadipocyte-derived adipocytes from both non-obese and obese patients (p < 0.001 vs. basal). In visceral preadipocyte-derived adipocytes, insulin did not increase basal glucose uptake. In subcutaneous preadipocyte-derived adipocytes from non-obese and obese patients, metformin alone increased glucose uptake to 2.7 +/- 0.2 (p < 0.001) and 2.1 +/- 0.1 fold (p < 0.001) respectively. Metformin increased glucose uptake in visceral preadipocyte-derived adipocytes from non-obese (1.7 +/- 0.1 fold vs. basal, p < 0.001) and obese (2.0 +/- 0.2 fold vs. basal, p < 0.001) patients. Combined treatment with metformin and insulin increased glucose uptake in subcutaneous preadipocyte-derived adipocytes from both non-obese and obese patients (p < 0.001 vs. insulin alone). In preadipocyte-derived adipocytes glucose uptake is induced by metformin independent of the fat depot origin of the preadipocytes (subcutaneous or visceral) and the obesity state of the patients (non-obese or obese). In adipocytes, metformin seems to induce glucose uptake independent of insulin suggesting an alternative mechanism of action of this drug.
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PMID:Metformin induces glucose uptake in human preadipocyte-derived adipocytes from various fat depots. 2038 Jun 57

The relationship between obesity, metabolic syndrome, diabetes and cancer has been recognized for many years. Multiple studies conducted in the last 20 years have identified molecular mechanisms responsible for this phenomenon. Elucidation of the important role of insulin, IGF receptor, mTOR and AMP-activated protein kinase in breast cancer biology has led to the development and subsequent clinical evaluation of novel targeted therapies, including IGF-1 receptor-specific antibodies or tyrosine kinase inhibitors and inhibitors of mTOR. There is also a growing interest in the use of metformin, which has been shown to possess antitumor activity resulting from activation of AMP-activated protein kinase and subsequent inhibiton of mTOR, as well as from decreased circulating insulin levels. Metformin has been shown to inhibit proliferation, invasion and angiogenesis of neoplastic cells and to overcome resistance of breast cancer to chemotherapy, hormonal therapy and HER2 inhibition. Recently, metformin has been demonstrated to inhibit breast cancer stem cell growth and to synergize with chemotherapy in suppression of tumor growth and prolongation of survival of breast tumor-bearing animals. Several currently ongoing Phase II and III clinical studies are evaluating the therapeutic efficacy of metformin in the treatment of early and advanced breast cancer patients.
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PMID:Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin. 2046 5

A high carbohydrate-high fat (HC-HF) diet-associated with hyperinsulinemia has been previously reported to induce accelerated growth of prostate cancer in a xenograft model. High energy supply and insulin/insulin growth factor-1 axis are two of the mechanisms proposed. We hypothesize that metformin may have a protective effect against prostate cancer progression by affecting metabolisms associated with high energy intake. In the present study, animals were randomized into five groups, receiving a HC-HF diet with 50, 100, or 250mg/kg body weight (mg/kg) metformin in drinking water, a standard diet or HC-HF diet alone. Animals on the HC-HF diet developed obesity and insulin resistance. They had significantly higher body weight, fasting blood glucose at an upper level of normal range, higher insulin secretion and utilization, and fatty degeneration of the liver. Metformin at the doses employed significantly reduced food and water consumption; however, only a dose of 250mg/kg showed a significant reduction in body weight gain and suppression of gluconeogenesis as well remarkably reduced insulin secretion. There was no observed metformin-related hepato-toxicity in any of the groups. In summary, metformin at various doses exhibits protective effects on the metabolic disorder caused by the HC-HF diet with the most effective protection at a dose of 250mg/kg. These effects may explain its translational role relating to its anti-neoplastic potential.
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PMID:Protective effect of metformin in CD1 mice placed on a high carbohydrate-high fat diet. 2057 2


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