Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Insulin resistance is a common metabolic disorder. It plays an important role in the metabolic syndrome (or syndrome X), type 2 diabetes, obesity and in the lipodystrophic syndromes recently described, associated with treatments of HIV disease and represent a worrying cardiovascular risk. However, its pathophysiology remains poorly understood in these situations. Syndromes of major insulin resistance, although rare, allow investigations of the mechanisms leading to alterations in the insulin transduction pathways. Mutations of the insulin receptor gene have been discovered in rare patients. Therefore alterations at the post-receptor level are probably causative in other cases. Furthermore, the role of body fat repartition seems determinant in the apparition of insulin resistance, as attested by the clinical characteristics of lipodystrophies, either congenital or acquired. The two lipodystrophic syndromes which molecular defect is identified are the familial partial lipodystrophy of the Dunnigan type, due to mutations of the lamin A/C gene, and the congenital generalized lipodystrophy, linked to alterations in the protein seipin. However, their physiopathology remains mysterious. Lamin A/C is indeed an ubiquitous nuclear protein, which is also mutated in a genetic squelettic and/or cardiac myopathy, and seipin is a protein of unknown function mainly expressed in brain. Progresses in the understanding of these syndromes, in particular lipodystrophies which can be considered as caricatural models of the metabolic syndrome, will probably allow to clarify the physiopathology of the more common forms of insulin resistance.
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PMID:[Major insulin resistance syndromes: clinical and physiopathological aspects]. 1183 62

The adipocyte-derived hormone leptin, which plays an important role in energy homeostasis, has been suggested to have an influence on bone development and remodeling. However, it is not clear from animal studies whether leptin is a stimulator or an inhibitor of bone growth. Cross-sectional studies in humans suggest that serum leptin levels are positively associated with bone mineral density (BMD), but these observations are not consistent, and whether this relationship is independent of obesity remains unclear. We therefore examined the effect of sc leptin administration on BMD and markers of bone turnover in two women, one with congenital generalized lipodystrophy and the other with acquired generalized lipodystrophy. Both patients had regular menstrual cycles. At baseline, the BMD for both patients, measured at the lumbar spine and total hip, was within 1 SD of the peak bone mass. There was no significant change in BMD in both patients after 16-18 months of leptin therapy. Similarly, concentrations of serum osteocalcin and bone-specific alkaline phosphatase or urinary excretion of deoxypyridinoline and N-telopeptides remained unchanged after 6-8 months of leptin therapy, suggesting no effects of leptin on osteoblastic or osteoclastic activity. Our preliminary data suggest that sc leptin replacement in hypoleptinemic patients with generalized lipodystrophy has no effect on the mature adult skeleton.
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PMID:Effect of subcutaneous leptin replacement therapy on bone metabolism in patients with generalized lipodystrophy. 1241 54

Leptin has been shown to have a wide repertoire of peripheral effects, some of which are mediated through the central nervous system and others that are induced through a direct action on target tissues. There is now evidence showing that leptin exerts some of its metabolic effects acting directly on peripheral tissues. The role of leptin has expanded from a narrow position in obesity to effects on biological processes, such as diabetes, appetite, thermogenesis, the immune system and reproduction. Here in a first part, we review preclinical evidence for direct effects on specific tissues (neurons, liver and muscle) and metabolic pathways. In a second part we review clinical evidence for leptin effects. In particular we review the effects of recombinant human leptin in lean, obese, diabetic subjects and in patients with congenital leptin deficiency or lipoatrophic diabetes. Additionally, while clinic leptin has not shown dramatic effects in obese/diabetic subjects with measurable serum leptin, in states of leptin deficiency treatment with leptin has been shown to have profound effects on body weight and appetite and insulin resistance.
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PMID:Leptin: from animals to humans. 1267 80

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by marked lack of body fat since birth, which results in striking muscular appearance. Patients develop extreme insulin resistance and its complications, such as diabetes, hyperlipidemia and fatty liver. Mutations in the BSCL2 (which encodes seipin, a protein of unknown function) and AGPAT2 (which encodes 1-acylglycerol-3-phosphate O-acyltransferase 2) genes have been reported in patients with CGL. AGPAT2 is a key enzyme involved in triglyceride and phospholipid biosynthesis and, thus, the discovery of AGPAT2 mutations has heightened interest in the biochemical pathways of triglyceride synthesis and their implications in human physiology and in the pathophysiology of obesity, lipodystrophies and other adipose tissue disorders. All enzymes involved in triglyceride synthesis, including AGPAT, have several known isoforms encoded by different genes. Assuming different substrate specificities of these enzymes, the human body might have many forms of triglycerides and phospholipids. Here, we discuss the significance of these in energy storage, in addition to the normal functioning of cell membranes.
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PMID:Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. 1282 27

Insulin resistance is common and plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). Precedents in biomedical research indicate that evaluation of monogenic syndromes can help to understand a common complex phenotype. Monogenic forms of insulin resistance, such as familial partial lipodystrophy, which results from mutations in either LMNA (encoding lamin A/C) or PPARG (encoding peroxisome proliferator-activated receptor gamma), and congenital generalized lipodystrophy, which results from mutations in either AGPAT2 (encoding 1-acylglycerol-3-phosphate O-acyltransferase) or BSCL2 (encoding seipin), can display features seen in the common metabolic syndrome. In addition, insulin resistance is seen in disorders associated with insulin receptor mutations, progeria syndromes and in inherited forms of obesity. Although insulin resistance in such rare monogenic syndromes could simply be secondary to fat redistribution and/or central obesity, the products of the causative genes might also produce insulin resistance directly, and might illuminate new causative mechanisms for insulin resistance in such common disorders as T2DM and obesity.
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PMID:Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome. 1451 35

Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia. Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting glucose (from 205 +/- 19 to 126 +/- 11 mg/dl; P < 0.001), HbA1c (from 9 +/- 0.4 to 7.1 +/- 0.5%; P < 0.001), triglycerides (from 1,380 +/- 500 to 516 +/- 236 mg/dl; P < 0.001), LDL (from 139 +/- 16 to 85 +/- 7 mg/dl; P < 0.01), and total cholesterol (from 284 +/- 40 to 167 +/- 21 mg/dl; P < 0.01). HDL was unchanged (from 31 +/- 3 to 29 +/- 2 mg/dl; P = 0.9). Liver volumes were significantly reduced (from 3,663 +/- 326 to 2,190 +/- 159 cm3; P < 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 +/- 3.6 to 57.4 +/- 3.4 kg; P = 0.02) and resting energy expenditure (from 1,929 +/- 86 to 1,611 +/- 101 kcal/24 h; P < 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.
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PMID:Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. 1598 99

Leptin is an adipocyte-derived hormone that primarily acts in the hypothalamus and plays a key role in the regulation of food intake, body weight, energy expenditure and neuroendocrine function. Leptin has direct peripheral effects on several tissues, and it may be independently involved in insulin secretion and action besides its effects on body weight regulation. Basal plasma leptin and insulin concentrations correlate with each other. Insulin and glucose appear to increase leptin secretion. In turn, leptin increases peripheral insulin sensitivity while decreasing insulin secretion from pancreatic beta cells. Leptin increases skeletal muscle glucose uptake and oxidation, and suppresses hepatic glucose output. Effects of leptin on lipid metabolism might reduce lipotoxicity and therefore contribute to the improvement of hepatic, skeletal and whole body insulin sensitivity. Leptin is the first adipokine used in the treatment of hypoleptinemic clinical disorders. Although leptin therapy has limited success in common obesity, it has impressive effects in congenital leptin deficiency, lipoatrophic diabetes and syndromes of severe insulin resistance. Leptin has been reported to ameliorate hyperinsulinemia and diabetes in the clinical setting of congenital leptin deficiency. It also improves hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia and hepatic steatosis in lipoatrophic diabetes. These promising results warrant clinical trials to test the hypothesis that leptin alone or with classical antidiabetic agents may potentially be beneficial in the treatment of hypoleptinemic non-obese individuals with glucose intolerance and diabetes. This review summarizes the clinical applications of leptin, particularly emphasizing the effects of leptin on glucose homeostasis.
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PMID:Rethinking leptin and insulin action: therapeutic opportunities for diabetes. 1623 42

We discuss the anatomy, physiology, and pathophysiology of epicardial adipose tissue and its relationship to coronary atherosclerosis. Epicardial fat stores triglyceride to supply free fatty acids for myocardial energy production and produces adipokines. It shares a common embryological origin with mesenteric and omental fat. Like visceral abdominal fat, epicardial fat thickness, measured by echocardiography, is increased in obesity. Epicardial fat could influence coronary atherogenesis and myocardial function because there is no fibrous fascial layer to impede diffusion of free fatty acids and adipokines between it and the underlying vessel wall as well as the myocardium. Segments of coronary arteries lacking epicardial fat or separated from it by a bridge of myocardial tissue are protected against the development of atherosclerosis in those segments. However, when epicardial fat is totally absent in congenital generalized lipodystrophy, coronary atherosclerosis can still occur. Macrophages are more numerous and densely packed in the periadventitial fat of human atherosclerotic coronary arteries with lipid cores than in that of fibrocalcific or nonatherosclerotic coronary arteries. In obese patients with multiple cardiovascular risk factors, epicardial fat around atheromatous coronaries secretes several proinflammatory cytokines and is infiltrated by macrophages, lymphocytes, and basophils. Epicardial adipokine expression in obesity without coronary atherosclerosis has not been determined. In nonobese patients, epicardial fat around atheromatous coronary arteries expresses proinflammatory cytokines but produces either less adiponectin, a vasoprotective adipokine, than fat around nonatheromatous coronaries or a similar amount compared with thoracic subcutaneous fat. Further studies should be done to test the hypothesis that adipokines produced by and released from human epicardial adipose tissue might contribute locally to the pathogenesis of coronary atherosclerosis.
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PMID:Human epicardial adipose tissue: a review. 1754 Jan 90

Lipin-1 deficiency in the mouse causes generalized lipodystrophy, characterized by impaired adipose tissue development and insulin resistance. Lipin-1 expression in differentiating preadipocytes is required for normal expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma and CCAAT enhancer binding protein alpha, and for the synthesis of triacylglycerol. The requirement of lipin-1 for adipocyte differentiation can be explained, in part, by its activity as the sole adipocyte phosphatidic acid phosphatase-1 enzyme, which converts phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol. Here we identify glucocorticoids as the stimulus for the induction of lipin-1 expression in differentiating adipocytes, and characterize a glucocorticoid response element (GRE) in the Lpin1 promoter. The Lpin1 GRE binds to the glucocorticoid receptor and leads to transcriptional activation in adipocytes and hepatocytes, as demonstrated by reporter gene transcription, electrophoretic mobility shift, and chromatin immunoprecipitation assays. This represents the first gene regulatory element identified to directly influence lipin-1 expression levels, and may modulate lipin-1 mRNA levels in adipose tissue and liver in conditions associated with increased local glucocorticoid concentrations in vivo, such as obesity and fasting.
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PMID:Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis. 1836 92

The adipocyte-derived hormone, leptin controls feeding behavior, augments fatty acid beta-oxidation in the skeletal muscle, attenuates insulin secretion but enhances whole body insulin sensitivity and glucose disposal, thereby serving as a promising therapeutic candidate for the treatment of insulin resistance and dyslipidemia. Along with other researchers, we demonstrated the clinical efficacy and safety of leptin in the treatment of diabetes and dyslipidemia for patients with generalized lipodystrophy. However, the clinical application of leptin has been hampered by the notion that leptin does not fully exert its metabolic effects in human obesity and diet-induced obese rodents. We found that the activity of skeletal muscle AMP-activated protein kinase (AMPK) parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Our data indicate that the activation of skeletal muscle AMPK is mediated by the hypothalamic melanocortin pathway. In fact, intracerebroventricular administration of melanocortin agonist, MT-II in mice robustly overcomes high-fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia, with a concomitant recovery of AMPK activity in skeletal muscle. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the co-administration of melanocortin antagonist, SHU9119 and in the KKA(y) mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin per se, but was markedly recovered by MT-II. Our data provide evidence for the critical role of the central melanocortin system in leptin-skeletal muscle AMPK axis, and highlight the system as a therapeutic target for leptin insuffciency in obese humans.
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PMID:Hypothalamic melanocortin signaling and leptin resistance--perspective of therapeutic application for obesity-diabetes syndrome. 1939 82


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