Subject(s)
Cell Cycle , Nobel Prize , History, 21st Century , Medical Oncology/history , United Kingdom , United StatesSubject(s)
Colonic Neoplasms/diagnosis , Diet , Occult Blood , False Positive Reactions , Guidelines as Topic , Humans , Mass ScreeningSubject(s)
Diabetes Mellitus/epidemiology , Obesity , Adult , Australia/epidemiology , Body Mass Index , Humans , Prevalence , United StatesSubject(s)
Heart/embryology , Stem Cells/physiology , Animals , Cell Differentiation , Humans , MiceSubject(s)
Air Pollution/adverse effects , Myocardial Infarction/etiology , Urban Population , Boston , Humans , RiskABSTRACT
Chronic cold exposure stimulates sympathetically driven thermogenesis in brown adipose tissue (BAT), resulting in fat mobilization, weight loss, and compensatory hyperphagia. Hypothalamic neuropeptide Y (NPY) neurons are implicated in stimulating food intake in starvation, but may also suppress sympathetic outflow to BAT. This study investigated whether the NPY neurons drive hyperphagia in rats that have lost weight through cold exposure. Rats exposed to 4 degrees C for 21 days weighed 14% less than controls maintained at 22 degrees C (P < 0.001). Food intake increased after 3 days and remained 10% higher thereafter (P < 0.001). Increase BAT activity was confirmed by 64, 96, and 335% increases in uncoupling protein-1 mRNA at 2, 8, and 21 days. Plasma leptin decreased during prolonged cold exposure. Cold-exposed rats showed no significant changes in NPY concentrations in any hypothalamic regions or in hypothalamic NPY mRNA at any time. We conclude that the NPY neurons are not activated during cold exposure. This is in contrast with starvation-induced hyperphagia, but is biologically appropriate since enhanced NPY release would inhibit thermogenesis causing potentially lethal hypothermia. Other neuronal pathways must therefore mediate hyperphagia in chronic cold exposure.
Subject(s)
Acclimatization , Body Temperature Regulation , Feeding Behavior , Hyperphagia/physiopathology , Hypothalamus/physiopathology , Neuropeptide Y/metabolism , Proteins/metabolism , Animals , Body Weight , Cold Temperature , Hypothalamus/metabolism , Leptin , Male , Neurons/physiology , Neuropeptide Y/biosynthesis , Obesity , RNA, Messenger/biosynthesis , Rats , Rats, Wistar , Time Factors , Transcription, GeneticABSTRACT
Acute cold exposure which significantly stimulated thermogenesis in brown adipose tissue (BAT), also increased neuropeptide Y (NPY) levels in its hypothalamic sites of release without affecting NPY synthesis, suggesting that NPY release is acutely inhibited. To clarify whether these changes in NPY are the cause or consequence of BAT activation, we studied whether hypothalamic NPY and NPY mRNA levels in rats were affected by acute intraperitoneal injection of the beta 3-adrenoceptor agonist BRL 35135 (500 micrograms/kg), which directly activates BAT thermogenesis. BRL 35135 treatment doubled BAT uncoupling protein mRNA levels (p < 0.05), and increased core temperature by 0.4 degree C (p < 0.05), but neither hypothalamic regional NPY levels nor hypothalamic NPY mRNA levels were affected by BRL 35135. This suggests that the NPY changes induced by cold exposure are not the result of BAT activation, and is consistent with the hypothesis that decreased NPY release during cold exposure might disinhibit the sympathetic innervation that drives BAT thermogenesis.
Subject(s)
Adipose Tissue, Brown/metabolism , Body Temperature Regulation , Cold Temperature , Hypothalamus/metabolism , Neuropeptide Y/metabolism , Adrenergic beta-Agonists/pharmacology , Animals , Blotting, Northern , Body Temperature/drug effects , Carrier Proteins/genetics , Carrier Proteins/metabolism , Eating/drug effects , Ion Channels , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mitochondrial Proteins , Neuropeptide Y/biosynthesis , Neuropeptide Y/genetics , Phenethylamines/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Wistar , Uncoupling Protein 1ABSTRACT
The fatty Zucker rat has impaired heat production and fails to mount an adequate thermogenic response to cold exposure, partly because of decreased sympathetic drive to thermogenesis in brown adipose tissue. Neuropeptide Y, synthesized in neurons of the hypothalamic arcuate nucleus and released in the paraventricular nucleus, stimulates feeding and inhibits brown adipose tissue activity. The neuropeptide Y neurons are overactive in fatty Zucker rats and are thought to contribute to hyperphagia, reduced energy expenditure and obesity. We have examined the relationship between thermogenic activity in brown adipose tissue (measured as uncoupling protein messenger RNA levels) and hypothalamic neuropeptide Y and neuropeptide Y messenger RNA levels in response to cold exposure (4 degrees C) for 2.5 and 18 h, in fatty and lean Zucker rats. In lean Zucker rats, cold exposure at 4 degrees C for 2.5 and 18 h significantly increased uncoupling protein messenger RNA levels by 3.5-fold (P<0.01) and 3.3-fold (P<0.01), respectively, compared with warm-maintained controls. Exposure to cold for 18 h also increased neuropeptide Y concentrations in the paraventricular nucleus (P<0.01) and ventromedial nucleus (P<0.001) in lean rats, with no change in neuropeptide Y messenger RNA after either 2.5 or 18 h. By contrast, fatty Zucker rats showed no significant changes in uncoupling protein messenger RNA (P>0.05) at either duration of cold exposure. There were also no significant changes in neuropeptide Y levels in any region nor in neuropeptide Y messenger RNA, with cold exposure for either period (P>0.05). In lean rats, cold exposure therefore stimulates brown fat uncoupling protein messenger RNA and also increases neuropeptide Y concentrations in its hypothalamic sites of release. We suggest that increased brown fat thermogenic capacity induced by cold in lean rats may be mediated, at least in part, by decreased neuropeptide Y release in the paraventricular nucleus, resulting in its accumulation in this site. Defective thermogenic responses in fatty rats may result from central dysregulation of brown adipose tissue due to sustained and non-suppressible overactivity of hypothalamic neuropeptide Y neurons.
