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

Diabetes, known since antiquity, has been defined by glycosuria. In 1886, when Minkowski demonstrated that pancreatectomized dogs developed diabetes, the islets of Langerhans became a focus of the search for an active principle culminating in the discovery and the isolation of insulin in 1921 by Banting, Best and Collip. In 1959, the radioimmunoassay of Yalow and Berson solidified the concept of insulin resistance in non-insulin dependent diabetes (NIDDM). In 1971, the insulin receptor was defined as a cell surface protein that initiated the insulin signal transduction cascade. Today, we know that NIDDM accounts for at least 90% of all diabetes worldwide and involves approximately 100 million people. The microvascular complications of NIDDM are the same as for insulin dependent diabetes (IDDM) and are related to the intensity and duration of hyperglycaemia. Further, it is clear from the Diabetes Control and Complications Trial (DCCT) that all microvascular complications can be reduced with intensive control of the blood glucose. Macrovascular disease is also accelerated in NIDDM, including both hypertension and dyslipidemia. The major risk factor for NIDDM are age, obesity, physical inactivity, and genetic background. The earliest features seen in individuals destined to develop NIDDM is insulin resistance, but for hyperglycaemia to ensure there must be a defect in insulin secretion. Thus, insulin resistance defines the prehyperglycaemic phase of NIDDM, but varying degrees of insulin secretory deficiency define the hyperglycaemic phase. Macrovascular risk occurs throughout the lifetime of the individual, whereas microvascular risk ensues with the inception of hyperglycaemia. Tomorrow, we will understand more clearly whether lifestyle changes, such as diet and exercise, or new classes of drugs, can delay or prevent NIDDM. Clinical trials are now beginning to test whether impaired glucose tolerance (IGT) can be delayed or prevented from moving to overt NIDDM. The genetics of NIDDM are under intense study. Mutations in the insulin receptor lead to NIDDM in a small number of patients, and mutations in the glucokinase gene lead to maturity onset diabetes of the young (MODY). Work is now underway to study other candidate genes as well as work on positional cloning techniques to identify diabetes genetic loci. The hormone Leptin has just been discovered and is a major regulator of body weight. In summary, the most important new emphasis on the treatment of NIDDM is the recognition of the importance of hyperglycaemia and our ability to both treat and possibly prevent this metabolic perturbation. This joins the longer-term emphasis on cardiovascular risk reduction from both treatment and prevention of hypertension and dyslipidemia.
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PMID:Non-insulin dependent diabetes--the past, present and future. 928 27

A reduction in fat intake may be achieved by making educated choices to reduce total calorie intake, to consume a lower quantity of total fats, or to modify the ratio of saturated-to-polyunsaturated lipids. Leptin agonists or NPY or CCK antagonists may prove to be useful to diminish appetite and thereby reduce the total intake of food. But eating has such cultural, social, and hedonistic attributes that such a single-pronged approach is unlikely to be successful. The use of fat substitutes may prove to be popular to provide a wide range of snack food options, but these are likely to be of minimal use in weight reduction programs because of their distribution of additives in only a limited number of foods. The inhibitors of lipid digestion will be modestly successful in the short term; their long-term success will be influenced by gastrointestinal adverse effects and the need to consume fat-soluble vitamin supplements to prevent the development of fat-soluble vitamin deficiencies. The inhibition of lipid absorption is an attractive targeted approach for the treatment of obesity, since this would reduce the uptake of visible as well as invisible fats, which would potentially offer convenient dosing, and could also be a means to inhibit secondarily the uptake of carbohydrate calories.
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PMID:Inhibition of lipid absorption as an approach to the treatment of obesity. 930 43

Leptin, the ob gene product, is released from adipose tissue and likely acts in the central nervous system, particularly within the hypothalamus, to exert many of its effects. Obesity in C57BL/6J ob/ob mice is caused by a mutation in the ob gene resulting in a lack of functional leptin. In this study, we first compared effects of a single intracerebroventricular (ICV) injection of 3 pmol (50 ng) or 60 pmol (1 microg) leptin on food intake and oxygen consumption of lean and ob/ob mice deprived of food for 4 h during the 48-h period postinjection. Injection of 3 pmol leptin minimally lowered food intake in these mice without influencing oxygen consumption. Injection of 60 pmol of leptin rapidly lowered food intake within 30 min in both lean and ob/ob mice, with effects persisting for 24 h. Lean and ob/ob mice treated with leptin consumed 40 and 60% less food, respectively, in 24 h than vehicle-treated controls. Injection of leptin (60 pmol ICV) suppressed food intake of adrenalectomized mice as well (by 25 and 40% in lean mice and by 20 and 68% in ob/ob mice at 3 and 24 h, respectively), indicating that glucocorticoids are not essential for leptin to suppress food intake. Leptin increased oxygen consumption in conditions in which diet-induced thermogenesis was low, i.e., in fed ob/ob mice and in food-deprived lean mice, but not in fed adrenalectomized ob/ob mice or in fed lean mice. ICV injection of 60 pmol leptin along with 230 pmol (2 microg) of neuropeptide Y (NPY) attenuated NPY-induced feeding in ob/ob, but not in lean mice, suggesting an enhanced potential for crosstalk between the leptin and NPY signaling systems in ob/ob mice lacking endogenous leptin. Leptin exerts rapid-onset actions within the central nervous system to coordinate control of food intake and metabolic rate.
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PMID:Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. 931 66

Body weight is tightly regulated physiologically. The recent discovery of the peptide hormone leptin has permitted more detailed evaluation of the mechanisms responsible for control of body fat. Leptin is almost exclusively produced by adipose tissue and acts in the CNS through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, and endocrine function. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Studies from our laboratory suggest that leptin also increases sympathetic nerve activity to kidney, hindlimb, and adrenal gland. However, systemic administration of leptin does not acutely increase arterial pressure or heart rate in anesthetized animals. Thus, longer-term exposure to hyperleptinemia may be necessary for full expression of the expected pressor effect of renal sympathoexcitation. Alternatively, leptin may have additional cardiovascular actions to oppose sympathetically mediated vasoconstriction. Leptin in high doses increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin appears to increase systemic insulin sensitivity, even in the absence of weight loss. Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.
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PMID:Sympathetic and cardiorenal actions of leptin. 932 91

Leptin, the product of the human OB gene, is increased in obese individuals, suggesting resistance to its effect. However, there is variability in leptin levels at each level of body mass index, suggesting that genetic and environmental factors other than overall adiposity may regulate leptin concentrations. Leptin concentrations are higher in women relative to men, a difference that is only partially explained by the increased fat depots in women. The authors hypothesized that higher estrogen levels in women might be responsible for the sexual dimorphism in leptin concentrations. To test this hypothesis, they measured leptin concentrations in premenopausal women not on oral contraceptives (PRE) (n = 53), postmenopausal women on hormone replacement therapy (POSTY) (n = 28), and postmenopausal women not on hormone replacement therapy (POSTN) (n = 28) in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors. Analyses were restricted to nondiabetic Mexican Americans. Subjects were well matched on obesity as assessed by body mass index (kg/m2): PRE = 31.0, POSTY = 29.8, and POSTN = 31.6. Leptin concentrations (ng/ml) were not significantly different among the three groups (PRE = 27.6, POSTY = 28.3, and POSTN = 27.8). The authors conclude that differences in estrogen levels are not likely to explain the sexual dimorphism in leptin concentrations.
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PMID:Leptin concentrations in women in the San Antonio Heart Study: effect of menopausal status and postmenopausal hormone replacement therapy. 932 36

Over the last century there has been a trend toward an earlier onset of menarche attributed to better nutrition and body fatness. With the discovery of the obesity gene and its product, leptin, we reexamined this hypothesis from a new perspective. As delayed menarche and leanness are considered risk factors for osteoporosis, we also evaluated the relation between leptin and bone mass. Body composition and serum leptin levels were measured, and the timing of menarche was recorded in 343 pubertal females over 4 yr. Body composition was measured by dual x-ray absorptiometry, and leptin by a new RIA. All participants were premenarcheal at baseline (aged 8.3-13.1 yr). Leptin was strongly associated with body fat (r = 0.81; P < 0.0001) and change in body fat (r = 0.58; P < 0.0001). The rise in serum leptin concentration up to the level of 12.2 ng/mL (95% confidence interval, 7.2-16.7) was associated with the decline in age at menarche. An increase of 1 ng/mL in serum leptin lowered the age at menarche by 1 month. A serum leptin level of 12.2 ng/mL corresponded to a relative percent body fat of 29.7%, a body mass index of 22.3, and-body fat of 16.0 kg. A gain in body fat of 1 kg lowered the timing of menarche by 13 days. Leptin was positively related to bone area (r = 0.307; P < 0.0001) and change in bone area (r = 0.274; P < 0.0001). A critical blood leptin level is necessary to trigger reproductive ability in women, suggesting a threshold effect. Leptin is a mediator between adipose tissue and the gonads. Leptin may also mediate the effect of obesity on bone mass by influencing the periosteal envelope. This may have implications for the development of osteoporosis and osteoarthritis.
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PMID:Leptin is inversely related to age at menarche in human females. 932 46

Leptin is the product of OB gene. This 16 kDa protein is produced by mature adipocytes and is secreted in plasma. Its plasma levels are strongly correlated with adipose mass in rodents as well as in humans. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. It has been suggested that leptin could be the link between obesity and diabetes. Recent experiments in rodents have shown that leptin expression in adipocytes is also regulated at short-term by hormones and nutrients. Leptin expression increases after food intake and decreases during fasting and diabetes. Insulin and glucocorticoids increase leptin expression, whereas catecholamines, via beta-adrenergic receptors and cAMP, and long-chain fatty acids (and thiazolidinediones), via PPARy, inhibit leptin expression. Leptin is a cytokine that binds to transmembrane receptors similar to the receptors of cytokine family (type IL-6), and transmit their information inside the cell, after dimerisation. A short-form of leptin receptor (with a cytoplasmic domain of 34 amino residues) has been identified in the choroid plexus. This type of receptor should be used for leptin transport across the blood-brain barrier. Then leptin binds to a long-form of leptin receptor in the hypothalamus (with a cytoplasmic domain of 302 amino residues) and decreases the production of neuropeptide Y, a neuromediator of food intake. The long-form of leptin receptor, transmits its information via the Janus Kinases (JAK) who subsequently phosphorylate transcription factors of the STAT family. Intermediary forms of leptin receptor have been identified in other tissues: liver, heart, skeletal muscles, endocrine pancreas. The role of leptin receptors in these tissues remains obscure, but is of considerable interest. Recent studies have shown that leptin inhibits insulin secretion and have anti-insulin effects on liver and adipose tissue. If these effects are confirmed, leptin could play a role similar to TNF alpha and could participate in the insulin-resistance of obesity and type II diabetes.
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PMID:Is leptin the link between obesity and insulin resistance? 934 38

Leptin is an adipocyte-derived blood-borne satiety factor that acts on its cognate leptin receptor (Ob-R) in the hypothalamus, thereby regulating food intake and energy expenditure. To explore whether mutations in the Ob-R gene cause obesity in humans, we have searched for mutations in the gene for Ob-Rb, a biologically active receptor isoform, in obese Japanese subjects. We have also examined associations between such mutants and obesity in the Japanese. Genomic DNAs were used as templates in polymerase chain reaction (PCR) with primers selected to amplify exons 2 to 20 of the human Ob-Rb gene. Direct sequence analysis of the PCR products revealed 7 nucleotide sequence variants (Lys109Arg, Gln223Arg, Ser343Ser, Ser492Thr, Lys656Asn, Ala976Asp, and Pro1019Pro) in the Ob-Rb coding region from 17 obese Japanese subjects with a family history of obesity (BMI 39.3 +/- 8.4 kg/m2). No missense and nonsense mutations were found such as those in Zucker fatty (fa/fa) rats and Koletsky (fa[k]/ fa[k]) rats. Nucleotide substitutions occurred at relatively high frequencies at codons 109, 223, 976, and 1019 (79, 91, 100, and 85%, respectively). Allele frequency of each variant determined by PCR-RFLP and PCR-single strand conformation polymorphism analyses showed no significant differences between 47 obese (BMI 35.1 +/- 6.5 kg/m2) and 68 non-obese (BMI 21.6 +/- 2.2 kg/m2) subjects. The present study represents the first report of sequence variants of the Ob-Rb gene in the Japanese and provides evidence against either obesity-causing mutations or association of sequence variants with obesity in obese Japanese subjects.
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PMID:Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity. 934 3

Leptin, a hormone secreted by adipose tissue in proportion to body adiposity, is proposed to be involved in the central nervous regulation of food intake and body weight. In addition, evidence is emerging that leptin regulates neuroendocrine and metabolic functions as well, presumably via its action in the central nervous system (CNS). To investigate this regulatory effect of leptin, we infused 3.5 microg of human leptin directly into the third cerebral ventricle (i3vt) of lean male Long-Evans rats, 90 min before the onset of their dark phase. Before and after infusion, blood samples were withdrawn through indwelling catheters for assessment of hormonal (plasma corticosterone, insulin, leptin), autonomic (plasma norepinephrine, epinephrine), and metabolic (plasma glucose) parameters. I3vt leptin caused an increase in plasma corticosterone and plasma leptin levels relative to the control condition. The effects of i3vt leptin on corticosterone secretion became particularly apparent after the onset of the dark phase. The results of the present study indicate that i3vt leptin stimulates the hypothalamo-pituitary-adrenal (HPA) axis, particularly when rats normally encounter their largest meals. These results are consistent with the possibility that high circulating leptin levels may underlie the increased activity of the HPA axis that is generally characteristic of human obesity and most animal models of obesity.
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PMID:Central leptin stimulates corticosterone secretion at the onset of the dark phase. 935 47

To assess the role of the human kidney in leptin metabolism, we measured renal leptin net balance and urinary leptin excretion in 16 normal postabsorptive volunteers with varying degrees of obesity. Arterial leptin concentrations (11.6 +/- 2.7 ng/ml) significantly exceeded renal vein concentrations (10.3 +/- 2.5 ng/ml, P < 0.001). Renal leptin fractional extraction averaged 13.1 +/- 1.1%, and renal leptin net balance (uptake) averaged 1,070 +/- 253 ng/min. Lineweaver-Burk analysis indicated that renal leptin uptake followed saturation kinetics with an apparent Michaelis-Menten constant of 10.9 ng/ml and maximal velocity of 1,730 ng/min. Leptin was generally undetectable in urine. Using literature values for systemic leptin clearance, we calculated that renal leptin uptake could account for approximately 80% of all leptin removal from plasma. These data indicate that the human kidney plays a substantial role in leptin removal from plasma by taking up and degrading the peptide.
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PMID:Role of the kidney in human leptin metabolism. 937 75


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