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)

NIDDM and obesity are characterized by decreased insulin-stimulated glucose uptake in muscle. It has been suggested that impaired glucose phosphorylation to glucose-6-phosphate, catalyzed in muscle by hexokinase (HK)II, may contribute to this insulin resistance. Insulin is known to increase HKII mRNA, protein, and activity in lean nondiabetic individuals. The purpose of this study was to determine whether defects in insulin-stimulated HKII expression and activity could contribute to the insulin resistance of obesity and NIDDM. Fifteen lean nondiabetic control subjects, 17 obese nondiabetic subjects, and 14 obese NIDDM patients were studied. Percutaneous muscle biopsies of the vastus lateralis were performed in conjunction with leg balance and local indirect calorimetry measurements before and at the end of a 3-h euglycemic-hyperinsulinemic clamp (40 or 240 mU x min(-1) x m[-2]). Leg glucose uptake in response to the 40-mU insulin infusion was higher in the lean control subjects (2.53 +/- 0.35 micromol x min(-1) per x 100 ml leg vol) than in obese (1.46 +/- 0.50) or NIDDM (0.53 +/- 0.25, P < 0.05) patients. In response to 240 mU insulin, leg glucose uptake was similar in all of the groups. In response to 40 mU insulin, HKII mRNA in lean control subjects was increased 1.48 +/- 0.18-fold (P < 0.05) but failed to increase significantly in the obese (1.12 +/- 0.24) or NIDDM (1.14 +/- 0.18) groups. In response to 240 mU insulin, HKII mRNA was increased in all groups (control subjects 1.48 +/- 0.18, P < 0.05 vs. basal, obese 1.30 +/- 0.16, P < 0.05, and NIDDM 1.25 +/- 0.14, P < 0.05). Under basal conditions, HKI and HKII activities did not differ significantly between groups. Neither the 40 mU nor the 240 mU insulin infusion affected HK activity. Total HKII activity was reduced in the obese subjects (4.33 +/- 0.08 pmol x min(-1) x g(-1) muscle protein) relative to the lean control subjects (5.00 +/- 0.08, P < 0.05). There was a further reduction in the diabetic patients (3.10 +/- 0.10, P < 0.01 vs. the control subjects, P < 0.01 vs. the obese subjects). Resistance to insulin's metabolic effects extends to its ability to induce HKII expression in obesity and NIDDM.
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PMID:Insulin-induced hexokinase II expression is reduced in obesity and NIDDM. 951 44

Massive obesity in males is associated with decreased total and free testosterone levels as well as elevated estradiol levels. The decrease in testosterone occurs without the compensatory increases in gonadotropin and a progressive hypogonadotropic hypogonadal cycle develops. During the hypogonadal state, there is a preferential deposition of abdominal adipose tissue. With the increasing fatty-tissue accumulation, there is an increase of aromatase activity that is associated with a greater conversion of testosterone to estradiol (testosterone-estradiol shunt). This results in further depression of testosterone concentrations and leads to the increased preferential deposition of abdominal fat that, in turn, leads to a progressive hypogonadal state. Testalactone, an aromatase inhibitor, interrupts this cycle and repairs the depressed testosterone concentrations and decreases estradiol levels. This increases the testosterone levels and reverses the preferential deposition of abdominal fat, while increasing muscle protein and fat-free mass.
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PMID:The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt--a major factor in the genesis of morbid obesity. 1034 71

One of the first steps in a clinical approach to any obese subject should be focused on the reduction and/or normalization of any potential or existing metabolic abnormality. Overeating and/or unbalanced food intake remains the major element in the origin and maintenance of obesity. The reduction of energy intake is the basis of successful weight loss. In obese subjects there are huge amounts of energy stored, mainly in the adipose tissue, which are mobilized according to the size and duration of an energy deficit. Considerable studies have been devoted to finding the optimal dietary approach that would promote rapid weight loss while maximizing the depletion of adipose tissue and conserving body protein. During fasting adipose tissue lipolysis rate increases and liberated unesterified fatty acids are oxidized in muscle and liver. The liver produces ketones which are oxidized in muscle and brain. The energy need of the brain is not sufficiently covered by ketone oxidation, therefore additional glucose must be provided. The liver produces glucose by gluconeogenesis using amino acids from muscle protein. Because of limited protein sources, protein must be given during energy restricted diet. Besides protein also vitamins, minerals, trace elements, fiber, and linoleic acid must be substituted during fasting and during treatment with very low calorie diets. Meal replacements are helpful to fulfil all the requirements. There is consensus that the first step in dietary treatment is an energy restricted diet with a calorie deficit of at least 600 Kcal/day, but more than 800 Kcal/day must be provided, with all essential nutrients. Observing the regulations, weight reduction with appropriate diet plans improves metabolic disturbances.
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PMID:[Principles of dietary treatment of obesity]. 1102 88

Rheumatoid arthritis is a debilitating, chronic, systemic, autoimmune disease of unknown etiology that causes destruction of joint cartilage and bone. It generally occurs between the fourth and sixth decades of life, and affects two to three times more women than men. It is characterized by joint stiffness, pain, and swelling, and is accompanied by a loss of body cell mass. This loss of cell mass, known as rheumatoid cachexia, predominates in skeletal muscle, but also occurs in the viscera and immune system. Thus, rheumatoid cachexia leads to muscle weakness and a loss of functional capacity, and is believed to accelerate morbidity and mortality in rheumatoid arthritis. Currently there is no established mechanism for rheumatoid cachexia, but it is accompanied by elevated resting energy expenditure, accelerated whole-body protein catabolism, and excess production of the inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta. Tumor necrosis factor-alpha is probably the central mediator of muscle wasting in rheumatoid arthritis, and is known to act synergistically with interleukin-1beta to promote cachexia. In general, tumor necrosis factor-alpha and interleukin-1beta are thought to alter the balance between protein degradation and protein synthesis in rheumatoid arthritis to cause muscle wasting. The precise mechanism by which they do this is not known. Reduced peripheral insulin action and low habitual physical activity are important consequences of rheumatoid arthritis, and have also been implicated as mediators of rheumatoid cachexia. Insulin inhibits muscle protein degradation. Consequently, reduced peripheral insulin action in rheumatoid arthritis is thought to be permissive to cytokine-driven muscle loss. The cause of reduced peripheral insulin action in rheumatoid arthritis is not known, but tumor necrosis factor-alpha has been shown to interfere with insulin receptor signaling and is probably an important contributor. Low habitual physical activity has consistently been observed in rheumatoid arthritis and is an important consequence of, and contributor to, muscle wasting. In addition, low physical activity predisposes to fat gain and is believed to precipitate a negative reinforcing cycle of muscle loss, reduced physical function, and fat gain in rheumatoid arthritis, which leads to 'cachectic obesity'. To date, there is no standard treatment for rheumatoid cachexia. However, physical exercise is currently believed to be the most important and clinically relevant countermeasure against rheumatoid cachexia. In general, a combination of skeletal muscle strength training and aerobic exercise is recommended, but must be prescribed with the patient's disease status, overall health, and safety in mind. Future studies should investigate the safety, efficacy, and required dose of anti-cytokine therapy for the treatment of rheumatoid cachexia. In this review, we outline the current definition of rheumatoid cachexia, and discuss the etiology, pathogenesis, and treatment of rheumatoid cachexia.
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PMID:Cachexia in rheumatoid arthritis. 1216 13

The purpose of this review is to summarize our current understanding of the acute and chronic interactions between alcohol and nutrient metabolism in skeletal muscle. Insulin is well known to play an important regulatory role in nutrient, especially glucose, uptake and utilization in skeletal muscle. Several studies have shown that alcohol can acutely reduce the normal metabolic responses of skeletal muscle to the action of insulin. The most obvious of these is an acute impairment in glucose metabolism associated with alcohol consumption. While the exact mechanism(s) underlying this acute insulin resistance is presently unclear, several possible factors are discussed in this review. In contrast to these short-term effects, the effects of alcohol on skeletal muscle insulin sensitivity in chronic alcohol abusers are not as well established. Chronic alcohol abuse is known to be associated with skeletal myopathies, believed to result from alcohol induced abnormalities in muscle protein synthesis. Finally, the alcohol-mediated impairments of many aspects of skeletal muscle metabolism are discussed in relation to the insulin resistance associated broad spectrum of common lifestyle-related disorders, including non-insulin dependent diabetes mellitus and obesity, the consequences of which may be important to the pathogenesis of alcohol-related diseases.
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PMID:Metabolic effects of alcohol on skeletal muscle. 1289 74

The putative influence of genomic factors on the responsiveness to nutrient intake is a newly developed field of research. As well, there is growing interest for determining the interactions between nutrient, inflammation and aging and the possible impact on lifespan and disease development. Inflammation adversely affects health in many diseases with an inflammatory basis, such as atherosclerosis, obesity and type 2 diabetes mellitus. The metabolic effects of inflammation are mediated by pro-inflammatory cytokines. Metabolic effects include insulin insensitivity, hyperlipidemia, muscle protein loss and oxidant stress. Aging is also characterized by an increase in inflammatory stress and contains some of the hallmarks of inflammatory disease. It is also a phase of life when inflammatory diseases rise in incidence. Evidence is accumulating that the individual level of cytokine production is influenced by single nucleotide polymorphisms (SNPs) in cytokine genes. The combination of SNPs might control the relative level of inflammatory stress following inflammatory stimuli and diseases. These genomic characteristics might therefore influence lifespan, morbidity and mortality in diseases with an infectious or inflammatory basis.Recent studies indicate that genotypic factors may influence the effectiveness of such immunonutrients as anti-oxidants and n-3 polyunsaturated fatty acids. A better understanding of this aspect of nutrient gene interactions and of the genomic factors which influence the intensity of inflammation in disease will help in the targeting of nutritional therapy.
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PMID:Genomic interactions with disease and nutrition. 1461 51

Diets with total protein intake >1.5 g.kg(-1).d(-1) and carbohydrate intake <150 g/d are effective for treatment of obesity, type 2 diabetes, and the Metabolic Syndrome. These diets improve body composition and enhance glycemic control. During weight loss, protein-rich diets reduce loss of lean tissue and increase loss of body fat. Specific mechanisms to explain each of these clinical outcomes remain to be fully elucidated. We propose that keys to understanding the relationship between dietary protein and carbohydrates are the relationships between the branched-chain amino acid leucine and insulin and glucose metabolism. Leucine is known to interact with the insulin signaling pathway to stimulate downstream signal control of protein synthesis, resulting in maintenance of muscle protein during periods of restricted energy intake. Leucine also appears to modulate insulin signaling and glucose use by skeletal muscle. Whereas total protein is important in providing substrates for gluconeogenesis, leucine appears to regulate oxidative use of glucose by skeletal muscle through stimulation of glucose recycling via the glucose-alanine cycle. These mechanisms produce protein sparing and provide a stable glucose environment with low insulin responses during energy-restricted periods.
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PMID:Potential importance of leucine in treatment of obesity and the metabolic syndrome. 1636 6

Fatty acid oversupply is a key mediator of skeletal muscle insulin resistance in obesity, primarily via accumulation of fatty acid metabolites and activation of proinflammatory pathways. Herein, we demonstrate that fatty acid-induced insulin resistance in humans is completely prevented the day after 1 session of endurance exercise. Because skeletal muscle is the primary site for systemic glucose disposal and is highly susceptible to impaired insulin action by elevated fatty acid availability, we obtained skeletal muscle samples to investigate possible mechanisms mediating this protective effect of exercise. Prevention of fatty acid-induced insulin resistance after exercise accompanied enhanced skeletal muscle protein expression of key lipogenic enzymes and an increase in muscle triglyceride synthesis. Partitioning more fatty acids toward triglyceride synthesis within muscle reduced the accumulation of fatty acid metabolites and suppressed the proinflammatory response in skeletal muscle, as evidenced by decreased phosphorylation and activation of JNK and increased abundance of inhibitor of NF-kappaB alpha (I kappa B-alpha) and I kappa B-beta. We believe this is the first study to demonstrate that 1 session of exercise completely reverses fatty acid-induced insulin resistance in humans. Reversal of insulin resistance accompanied enhanced lipogenic capacity within skeletal muscle, reduced accumulation of highly bioactive fatty acid metabolites, and suppressed activation of proinflammatory pathways known to impair insulin action.
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PMID:Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. 1751 Jul 9

Illnesses associated with insulin resistance exhibit increases in whole-body protein degradation and amino acid oxidation. However, the mechanisms stimulating muscle catabolism under these conditions are not clear. Because insulin resistance is associated with accumulation of lipids in muscle, we measured protein degradation in muscles of mice fed a high-fat diet. Muscle protein catabolism was accelerated on the high-fat diet, and this was associated with an increase in plasma free fatty acid and a decrease in plasma levels of the adipocyte-derived cytokine adiponectin. To evaluate how free fatty acids influence adiponectin-mediated changes in muscle protein breakdown we examined C2C12 skeletal muscle cells exposed to free fatty acids. Both saturated fatty acids (palmitate) and unsaturated fatty acids (oleate) increased protein degradation (25 and 18%, respectively) in part by activating the E3 ubiquitin ligases. Adenovirus-mediated overexpression of adiponectin blocked fatty acid-induced protein degradation in C2C12 cells. Palmitate activated the E3 ubiquitin ligases by suppressing insulin receptor substrate-1/Akt signaling in the C2C12 muscle cells, whereas adiponectin attenuated the E3 ubiquitin ligase activation by increasing both insulin receptor substrate-1 tyrosine phosphorylation and Akt Ser473 phosphorylation. In related experiments, adiponectin overexpression decreased TNFalpha and IL-6 expression in 3T3-L1 adipocytes, whereas exposure to free fatty acids had the opposite effect. We conclude that the balance between free fatty acids and adiponectin impacts muscle proteolysis in insulin-resistant conditions and suggest a role for adipose tissue-muscle cross talk in diabetes and obesity.
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PMID:Evidence for adipose-muscle cross talk: opposing regulation of muscle proteolysis by adiponectin and Fatty acids. 1776 67

The influence of obesity on protein dynamics is not clearly understood. We have designed experiments to test the hypothesis that obesity impairs the stimulation of tissue-specific protein synthesis after nutrient ingestion. C57BL/6J mice were randomized into 2 groups: group 1 (control, n = 16) was fed a low-fat, high-carbohydrate diet, whereas group 2 (experimental, n = 16) was fed a high-fat, low-carbohydrate diet ad libitum for 9 weeks. On the experiment day, all mice were fasted for 6 hours and given an intraperitoneal injection of (2)H(2)O. They were then randomized into 2 subgroups and either given a sham saline gavage or a liquid-meal challenge. Rates of protein synthesis were determined via the incorporation of [(2)H]alanine (5 hours postchallenge) into total gastrocnemius muscle protein, total liver protein, and plasma albumin. High-fat feeding led to an increase in total body fat (P < .001) and epididymal fat pad weights (P < .001) and elevated fasting plasma glucose levels (P < .01). Diet-induced obesity (a) did not affect basal rates of skeletal muscle protein synthesis, but did impair the activation of skeletal muscle protein synthesis in response to nutrient ingestion (P < .05), and (b) slightly reduced basal rates of synthesis of total hepatic proteins and plasma albumin (P = .10), but did not affect the synthesis of either in response to the meal challenge. In conclusion, there are alterations in tissue-specific protein metabolism in the C57BL/6J mouse model of diet-induced obesity. This model may prove to be helpful in future studies that explore the mechanisms that account for altered protein dynamics in obesity.
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PMID:Diet-induced obesity alters protein synthesis: tissue-specific effects in fasted versus fed mice. 1824 6


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