Increase In Brown Adipose Tissue Research Articles

Mechanisms of cachexia induced by T-cell leukemia in the rat

Body wasting (cachexia) is a common feature of cancer and a major cause of morbidity and mortality. The mechanisms underlying cachexia are largely unknown, and studies in experimental animals have focused mainly on solid tumors. Therefore, the objective of the present study was to quantify and investigate cachexia in experimentally induced T-cell leukemia in the rat. Induction of leukemia by serial passage (injection of cervical lymph node suspension) resulted in a rapid increase in white blood cell (WBC) count, hypertrophy of the spleen (by day 11), and severe morbidity within 17 to 18 days. Body weight gain and food intake declined steadily in leukemic animals from day 12, although weight loss was significantly greater in pair-fed, nonleukemie animals. However, leukemic rats had a lower body fat content and higher water content than pair-fed animals on day 18, so the measurement of body weight significantly underestimated the severity of cachexia. Resting oxygen consumption (Vo 2), measured during the light phase, declined in pair-fed animals from day 13, but was elevated in leukemic rats on days 12 to 18 by 25% ( P < .05, one-way ANOVA) compared with pair-fed rats and by 7% ( P < .05, one-way ANOVA) relative to free-feeding controls. Hypermetabolism was associated with an increase in brown adipose tissue (BAT) activity (74% and 89%, respectively, P < .05, one-way ANOVA) in leukemic rats compared with control and pair-fed groups. Effects of leukemia on Vo 2 and BAT were prevented by administration of the adrenergic antagonist, propranolol. These results indicate that T-cell leukemia in the rat results in rapid and severe cachexia, which is largely due to marked hypophagia, but is also accompanied by inappropriately high rates of energy expenditure that are mediated by sympathetic activation of BAT thermogenesis.

Dissociation of hypothalamic NPY from BAT uncoupling protein mRNA in rats exposed to 24 h thermoneutrality.

Neuropeptide Y (NPY) is increasingly considered to be involved in the central regulation of energy balance. Our previous studies suggest that hypothalamic NPY neurons of the arcuatoparaventricular (ARC-PVN) projection are inhibited in association with the marked increases in brown adipose tissue (BAT) thermogenesis and uncoupling protein (UCP) gene expression in rats exposed to cold. We therefore hypothesized that the NPYergic ARC-PVN system would be activated in a thermoneutral environment, when energy expenditure falls to a minimum, and that this activation could mediate the fall in BAT activity. We measured regional hypothalamic NPY concentrations, hypothalamic NPY receptor binding, and NPY mRNA together with UCP mRNA levels in rats exposed to thermoneutrality (29 degrees C) for 24 h. At thermoneutrality, UCP mRNA levels fell to 42% of those in controls maintained at 22 degrees C, but there were no significant changes in hypothalamic NPY or NPY mRNA levels or in NPY receptor binding. We conclude that the fall in UCP mRNA expression occurring under short-term thermoneutral condition is mediated by neuroendocrine mechanisms other than increased activity of hypothalamic NPY neurons.

1905 Capsaicin attenuates the noradrenaline-induced temperature increase in brown adipose tissue in the rat

E series prostaglandins (PGE) are known to elicit potent hyperthermia when injected into the anterior hypothalamic preoptic area (POAH) in rats, but the effector mechanisms mediating the rise in temperature are not well defined. In the present study, microinjection of PGE2 into the POAH dose-dependently increased non-shivering thermogenesis in brown adipose tissue (BAT) in urethananesthetized rats, bringing about a marked and sustained rise in interscapular BAT (IBAT) and core temperatures. The effect of intra-POAH PGE2 injection on IBAT and core temperatures could be blocked by systemic pretreatment with the sympathetic ganglionic blocker chlorisondamine chloride or the β-adrenergic receptor blocker propranolol, thus implicating the involvement of the sympathetic system. Furthermore, the increase in IBAT and core temperatures induced by intra-POAH PGE2 could be blocked by prior injection of the local anesthetic procaine or the GABA receptor agonist muscimol into the ipsilateral ventromedial hypothalamic nucleus (VMH). Taken together, the results suggest that PGE2 increases body temperature by acting in the POAH to stimulate heat production in BAT via a sympathetic efferent mechanism located in the VMH.

Defective regulation of thyroxine 5'-deiodinase in brown adipose tissue of ob/ob mice

Genetically obese (ob/ob) and lean (+/?) mice were exposed to a cold (14 degrees C) environment for 1, 3, 6, 12, 16, or 24 h or remained in a warm (28 degrees C) environment. In ob/ob mice the increase in brown adipose tissue (BAT) thermogenesis (mitochondrial GDP binding) was low and the increase in thyroxine 5'-deiodinase (T5'D) was delayed; there was a reduced increase in serum 3,5,3'-triiodothyronine (T3) level and these mice became hypothermic. Content of uncoupling protein (UCP) was low in BAT of obese mice and no cold-induced increase occurred. Adrenalectomy of obese mice before exposure to cold (14 degrees C) improved defective thermogenic response of BAT and thermoregulation, restored to normal the increases in T5'D activity and serum T3 level, and promoted an exaggerated increase in UCP content, detectable after only 6 h. Adrenalectomy of cold-exposed lean mice did not alter thermoregulation, the increase in BAT T5'D activity, or the increase in serum T3 but enhanced the thermogenic response and allowed a higher UCP content in BAT of cold-exposed mice. We conclude that suppression of the cold-induced increase in T5'D activity in BAT can be added to the other known corticosterone-dependent anomalies of the ob/ob mouse. We speculate that lack of the cold-induced increase in T5'D in BAT of the ob/ob mouse prevents the normal participation of T3 in the trophic response of BAT to cold and underlies the abnormality in this response.

Meal-induced brown fat thermogenesis and thyroid hormone metabolism in rats.

The relationship between the meal-induced increase in brown adipose tissue (BAT) thermogenesis, determined by the level of GDP binding to BAT mitochondria, and thyroid hormone metabolism have been examined. A single low-protein, high-carbohydrate meal resulted in a significant increase in the thermogenic activity of BAT. This effect on BAT thermogenesis was accompanied by significant increases in activity of thyroxine 5'-monodeiodinase in the BAT (P less than 0.05) and liver (P less than 0.02) but not with any significant changes in serum concentrations of the thyroid hormones. The stimulatory effects of the meal on BAT thermogenesis and hepatic thyroxine (T4) to triiodothyronine (T3) conversion persisted at least as late as 24 h after meal onset. Food deprivation for 40 h was associated with large reductions in serum concentrations of T3 (P less than 0.01) and T4 (P less than 0.001), but deprivation for 18 h had no significant effect on serum T3 and T4 concentrations. Our data indicate that the meal-induced increase in BAT thermogenesis can be independent from changes in serum concentrations of thyroid hormones and suggest that T3 produced in BAT in response to feeding may play a role in the thermic response of this tissue to meals.

Photoperiod and pinealectomy do not affect cold-induced deposition of brown adipose tissue in the long-evans rat

Brown adipose tissue is a major thermogenic effector of cold-induced nonshivering thermogenesis. Previous studies indicate that melatonin and/or short photo-period are involved in the increase in brown fat deposition seen in certain cold-acclimated rodents. The present study was undertaken, in part, to determine whether the pineal is a necessary component in the cold-induced increase in thermogenic capacity characteristic of the cold-acclimated laboratory rat. Under a 12L:12D light cycle, pinealectomized rats did not differ from sham-operated rats in their ability to increase brown fat deposition in the cold (5 °C). Moreover, in a subsequent set of experiments performed at 9 °C, intact rats maintained at a short photoperiod (9L:15D) exhibited the same degree of brown fat hypertrophy/hyperplasia as did those kept at a long photoperiod (15L:9D). These data thus indicate that: (a) the intact pineal is not necessary for the cold-induced increase in brown adipose tissue occurring in the cold-acclimated rat; and (b) photoperiod does not significantly modulate the magnitude of this increase.