Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.1.2.42 (DTA)
 1,693 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brown adipose tissue (BAT) has the capacity for uncoupled mitochondrial respiration and is proposed to be a key site for regulating energy expenditure in rodents. To better define the role of BAT in energy homeostasis, we previously created a line of transgenic mice with deficiency of BAT (UCP promoter-driven diphtheria toxin A transgenic mice [UCP-DTA]) mice. These mice develop obesity that initially is due to decreased energy expenditure and later accompanied by hyperphagia despite increased levels of circulating leptin. In addition, the obesity of these mice is accompanied by severe insulin-resistant diabetes and hyperlipidemia. To better define the basis for leptin resistance in this model, we treated UCP-DTA mice with leptin (300 microg i.p., b.i.d.) and compared their response with that of leptin-treated ob/ob and FVB control mice (30 microg i.p., b.i.d.). Leptin treatment of FVB and ob/ob mice decreased their body weight and food intake and improved their glucose homeostasis. In contrast, tenfold higher dosages of leptin had no effect on body weight, food intake, or circulating insulin or glucose concentrations of UCP-DTA mice. Hypothalamic neuropeptide Y (NPY) mRNA expression was lower in UCP-DTA mice than in littermate control FVB mice in the fed state, and increased progressively in response to food restriction as leptin levels fell. In parallel to the levels of hypothalamic NPY, corticosterone levels were initially suppressed and rose with food restriction. Thus food intake, body weight, and insulin and glucose homeostasis of UCP-DTA mice are all extraordinarily resistant to leptin, whereas hypothalamic NPY and the hypothalamopituitary adrenal (HPA) axis may remain under leptin control. Further elucidation of the mechanisms underlying leptin resistance in UCP-DTA mice may provide valuable insights into the basis for leptin resistance in human obesity.
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PMID:Severe leptin resistance in brown fat-deficient uncoupling protein promoter-driven diphtheria toxin A mice despite suppression of hypothalamic neuropeptide Y and circulating corticosterone concentrations. 951 18

The objective was to characterize the ability of control and transgenic brown adipose tissue (BAT)-ablated uncoupling protein diphtheria toxin A chain (UCP-DTA) mice to adjust food intake in relation to changes in environmental temperature and to assess the involvement of leptin in this adjustment. We measured serum leptin in mice from a previous study of UCP-DTA mice raised at thermoneutrality (35 degrees C) or at the usual rearing temperature (24 degrees C) from weaning [Melnyk, A., M. -E. Harper, and J. Himms-Hagen. Am. J. Physiol, 272 (Regulatory Integrative Comp. Physiol. 41): R1088-R1093, 1997] and extended the study by acclimating control and obese UCP-DTA mice at 18 wk of age to cold (14 degrees C) for up to 14 days. Leptin levels did not change in control mice at 14 degrees C; however, food intake increased threefold within 1 day and remained at this level. Serum leptin level was elevated in UCP-DTA mice at 24 degrees C compared with control mice at 24 degrees C; this elevated level decreased within 1 day at 14 degrees C and was not different from the level in control mice by 14 days. Food intake of UCP-DTA mice that were hyperphagic at 24 degrees C did not change during 7 days at 14 degrees C, then increased slowly. Similar low leptin levels were present in control mice raised at 24 or 35 degrees C and in UCP-DTA mice raised at 35 degrees C. Food intake of control mice raised at 24 degrees C was two times that of control mice raised at 35 degrees C. UCP-DTA mice raised at 35 degrees C ate the same low amount as control mice raised at 35 degrees C. UCP-DTA mice at 24 degrees C were hyperphagic relative to control mice at 24 degrees C yet had elevated leptin levels in their serum. Two principal conclusions are drawn. First, adjustment of food intake over a fourfold range by control mice acclimated to temperatures from 35 down to 14 degrees C is independent of changes in serum leptin levels. Second, this adjustment of food intake in relation to temperature is defective in the UCP-DTA mouse; the defect leads to hyperphagia at 24 degrees C and a failure to increase food intake as rapidly as control mice when exposed to 14 degrees C. Because lack of UCP-1-mediated thermogenesis in BAT of knockout mice is known not to induce hyperphagia, we propose that deficiency of UCP-1-expressing brown adipocytes in BAT of UCP-DTA mice results in lack of a satiety factor, secreted by these cells in BAT of control mice in inverse relationship to sympathetic nervous system activity.
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PMID:Temperature-dependent feeding: lack of role for leptin and defect in brown adipose tissue-ablated obese mice. 957 79

Melanin concentrating hormone (MCH) and the orexins (A and B) have been identified as neuropeptides localized to the lateral hypothalamic area (LHA) and are potential regulators of energy homeostasis. Potential factors regulating expression of both MCH and the orexins include fasting and leptin. Previous studies have generated conflicting data and, as there is little leptin receptor expressed in the lateral hypothalamus, it is likely that any observed leptin effects on these peptides are indirect. In this study, we examined MCH and preproorexin expression in mice in physiological states of starvation, with or without leptin administration, in addition to characterizing MCH and preproorexin expression in well-known obesity models, including ob/ob and UCP-DTA mice. Neuropeptide Y (NPY) expression in the arcuate nucleus was used as a positive control. After a 60-h fast, expression of both NPY and MCH mRNA was increased (by 148 and 33%, respectively) while preproorexin expression in the murine LHA did not change. Leptin administration to fasted mice blunted the rise in MCH and NPY expression towards control levels. In contrast, there was a 78% increase in preproorexin expression in fasted mice in response to peripheral leptin administration. MCH expression was increased (by 116%) in ob/ob mice at baseline, as we have previously reported. In addition, leptin treatment of ob/ob mice blunted the increase in MCH expression. In contrast, preproorexin expression did not differ in the leptin-deficient ob/ob mice or in the obese hyperleptinemic brown adipose tissue deficient (UCP-DTA) mice in comparison with controls. In summary, MCH expression is increased in two states of decreased leptin, fasting and ob/ob mice, and leptin replacement blunts MCH expression in both paradigms. Thus, MCH expression appears to be regulated by leptin. In contrast, preproorexin expression does not respond acutely to fasting, although it is acutely increased by leptin treatment during fasting. These preproorexin responses are in contrast to those seen with well-characterized orexigenic neuropeptides, such as NPY and AgRP, suggesting that appetite regulation may not be a significant physiological role of orexins. This conclusion is further supported by the observation that orexin ablated mice have arousal and not feeding deficits.
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PMID:Characterization of melanin concentrating hormone and preproorexin expression in the murine hypothalamus. 1125 73