Brown Adipose Tissue DNA Research Articles

Interactions among chronic cold, corticosterone and puberty on energy intake and deposition

We have shown that chronic cold stress strongly interacts with corticosterone (B) to determine subsequent regulation of the hypothalamo-pituitary-adrenal (HPA) axis responses to novel stress. These studies, using the same 2 sets of rats, show that chronic cold also interacts with B and testosterone on signals of energy balance. The two groups of rats differed in weight by 20% and in age by 2 weeks (44–59 days of age). Adrenalectomized rats, replaced with varying doses of B, were exposed to cold or served as controls. Food intake and body weight during the experiments and hormones, metabolites and fat depots were measured on day 5. B, but not cold, affected food intake in the younger rats; by contrast, cold, but not B, affected food intake in the older rats. Testosterone was higher in older control rats and was markedly depressed by cold; younger rats had lower testosterone that was minimally affected by cold. Weight gain decreased in all rats at room temperature with increasing B, whereas they all lost weight in cold independently of B. Cold stimulated and B inhibited interscapular brown adipose tissue DNA content (reflecting sympathetic stimulation of thermogenesis). B stimulated insulin, whereas cold inhibited leptin and insulin; B also increased white adipose tissue weight gain in controls and inhibited its loss in cold. Leptin was unrelated to white adipose tissue depots in older control rats but was strongly related to these stores in younger rats and in all rats in cold. We conclude that: 1. By decreasing signals that act centrally to inhibit food intake (insulin, leptin and testosterone) cold allows B to stimulate food intake; 2. B inhibits weight gain although it causes accrual of fat; 3. Cold, probably through sympathetic stimulation of white adipose tissue, causes fat loss which is modulated by the inhibitory effect of B on sympathetic outflow; and, 4. The slope of the relationship between fat depot size and leptin becomes flatter in cold, possibly because of increased sympathetic outflow to these depots.

Metabolic alterations associated with the antidiabetic effect of beta 3-adrenergic receptor agonists in obese mice

Treatment of obese (ob/ob) mice with the beta 3-adrenergic receptor (beta 3-AR) agonist BRL-35135 (1 mg.kg body wt-1.day-1 for 20 days) normalized plasma glucose levels and significantly decreased plasma insulin and nonesterified fatty acid levels. The time frame for the hypoglycemic effect, which reached a maximum after 10 days of treatment, paralleled an increase in brown adipose tissue DNA and protein content. The basal level of mRNA for the beta 3-AR and mitochondrial uncoupling protein was found to be markedly decreased in the ob/ob animals relative to the lean group. Chronic treatment of ob/ob mice for 20 days resulted in a twofold increase in beta 3-AR mRNA and a fivefold increase in uncoupling protein mRNA in brown adipose tissue relative to the placebo group. These findings indicate that chronic treatment of ob/ob animals with a beta 3-AR agonist results in proliferation of brown adipose tissue, with an upregulation of the beta 3-AR, which is associated with a decrease in plasma glucose, insulin, and nonesterified fatty acid levels.

Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue.

Brown adipose tissue (BAT) contains glucocorticoid receptors; glucocorticoids are required for maintaining differentiated BAT in culture. These studies were performed to determine the effects of corticosterone on BAT thermogenic function and lipid storage. Rats were adrenalectomized and given subcutaneous corticosterone pellets in concentrations that maintained plasma corticosterone constant across the range of 0-20 micrograms/dl or were sham adrenalectomized. All variables were examined 5 days after surgery and corticosterone replacement. Measures of BAT function-thermogenic capacity [guanosine 5'-diphosphate (GDP) binding and uncoupling protein (UCP; a BAT-specific thermogenic protein)] and storage (BAT wet wt, protein, and DNA levels) were made. Plasma hormones (corticosterone, adrenocorticotropic hormone, insulin, 3,3',5-triiodothyronine, and thyroxine were measured. Corticosterone significantly affected BAT thermogenic measures: UCP content and binding of GDP to BAT mitochondria decreased with increasing corticosterone; GDP binding characteristics in BAT from similarly prepared rats examined by Scatchard analysis showed that maximum binding (Bmax) and dissociation constant (Kd) decreased with increasing corticosterone dose. BAT DNA was increased by adrenalectomy and maintained at intact levels with all doses of corticosterone; BAT lipid storage increased dramatically at corticosterone values higher than the daily mean level in intact rats. Histologically, the number and size of lipid droplets within BAT adipocytes increased markedly with increased corticosterone. White adipose depots were more sensitive to circulating corticosterone concentrations than were BAT depots and increased in weight at levels of corticosterone that were at or below the daily mean level of intact rats. We conclude that, within its diurnal range of concentration corticosterone acts to inhibit nonshivering thermogenesis and increase lipid storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of immobilization stress on in vitro and in vivo thermogenesis of brown adipose tissue.

Repetitive intermittent stress such as immobilization has been shown to induce an improved cold tolerance through an enhanced capacity of nonshivering thermogenesis (NST), causing positive cross adaptation between nonthermal stress and cold. In the present study, effect of 3-h-daily immobilization stress for 4-5 weeks was investigated on in vitro and in vivo thermogenesis of interscapular brown adipose tissue (BAT). In vitro thermogenesis was measured in the minced tissue blocks incubated in Krebs-Ringer phosphate buffer with glucose and albumin at 37 degrees C, using a Clark-type oxygen electrode. The stressed rats showed less body weight gain during the experiment. The BAT weight, its protein and DNA contents were significantly greater in the stressed rats. Basal, noradrenaline- and glucagon-stimulated oxygen consumptions were significantly greater in the stressed rats. In vivo thermogenesis was assessed by the changes of temperatures in colon (Tcol), BAT (TBAT), and tail skin (Tsk) induced by noradrenaline or glucagon infusion in the anesthetized rats. Noradrenaline and glucagon increased the TBAT and the extent of increase was greater in the stressed rats. These results indicate that cross adaptation between nonthermal stress and cold may be mediated through an enhanced thermogenic activity of BAT.

Effects of neonatal sympathectomy on brown fat development and susceptibility to high fat diet induced obesity in mice

Injections of 6-hydroxydopamine in mouse neonates caused extensive and long lasting damage to the sympathetic nervous system and impaired brown fat development. Brown adipose tissue (BAT) thermogenic capacity of sympathectomized mice (up to 120 days old) was reduced because of marked reductions in the tissue mitochondrial protein content and the mitochondrial concentration of uncoupling protein, as assessed by [3H]GDP binding and immunoassay. Neonatal sympathectomy did not affect BAT DNA content. Sympathectomized mice also had reduced epinephrine-stimulated rates of oxygen consumption. BAT of sympathectomized mice failed to respond by increases in [3H]GDP binding to isolated mitochondria and uncoupling protein concentration when animals were offered a palatable high-fat dietary supplement that increased calorie intake of both normal and sympathectomized mice. The high-fat diet caused increases in body weight, carcass fat, and gonadal white fat pad weights in sympathectomized animals that were similar to those of control mice. These results show that inactivation of BAT metabolism did not accentuate the development of obesity caused by a dietary supplement rich in fat and suggest that stimulation of BAT metabolism was not very effective in counteracting the obesity-inducing effect of this diet.

Insulin and metabolic efficiency in rats. II. Effects of NE and cold exposure

The role of insulin in metabolic efficiency (ME, i.e., efficiency of body wt gain) was examined under conditions of maximal energy expenditure in control and diabetic rats. Long-lasting insulin was administered using a protocol that did not affect food intake and increased ME in both groups. Half the animals were injected chronically with norepinephrine (NE). NE alone in controls decreased body weight and ME and increased brown adipose tissue (BAT) growth, thermogenic potential [cytochrome c oxidase activity (COA)], and lipoprotein lipases (LPL) activity; however, in diabetics, body weight, ME, and food intake all decreased and only BAT LPL activity and DNA content increased. The combination of NE and insulin increased BAT protein and COA in diabetics; in controls, all BAT measures were further increased and ME was intermediate to that of either treatment alone. Cold exposure decreased body weight and ME, increased food intake and qualitatively produced similar increases in BAT growth, COA, and LPL activity in both controls and diabetics. In diabetics, combined cold exposure and insulin did not affect the increase in BAT growth or LPL activity resulting from either treatment alone, but in controls this combination decreased BAT growth and COA. It is concluded that, even under conditions of maximal energy expenditure, both extremes of basal insulin status result in decreased BAT growth and thermogenic potential, but have opposite effects on ME.

Effects of fasting and food restriction on brown adipose tissue composition in normal and dystrophic hamsters.

Fasting for 36-48 h or food restriction (30% reduction of daily food intake for 6 weeks) caused brown adipose tissue (BAT) atrophy in hamsters. Fasting-induced atrophy was characterized by reductions in tissue mass, DNA, protein, and thermogenin. By contrast, food restriction had no effect on tissue cellularity (DNA) but markedly reduced the tissue protein and thermogenin contents. The concentration of thermogenin in isolated mitochondria was unchanged by fasting or food restriction. Dystrophic hamsters had a reduced BAT mass when compared with weight-matched control hamsters. This resulted from a reduction in tissue cellularity since BAT DNA, protein and thermogenin contents were all reduced. The extent of binding of [3H]guanosine diphosphate to isolated mitochondria and their content of thermogenin were similar in normal and dystrophic hamsters. In response to cold exposure, as in normal hamsters, BAT of dystrophic hamsters grew and the tissue thermogenin increased, but the mitochondrial concentration of thermogenin did not change. In response to fasting, in contrast with normal hamsters, there was no significant reduction in BAT DNA in dystrophic animals and the loss of tissue protein was reduced. However, the relative changes in BAT composition during chronic food restriction were similar in normal and dystrophic animals. Thus, reduction in hamster BAT thermogenic capacity during food deprivation may occur by loss of cells and (or)reduction in the tissue protein and thermogenin contents. The extent of protein and (or) DNA loss may be dependent upon the original tissue mass and the severity of food deprivation.

Effects of sucrose feeding and denervation on lipogenesis in brown adipose tissue

Rats were fed standard laboratory chow or sucrose + chow for 2–3 weeks. Sucrose feeding significantly increased the size and norepinephrine content of interscapular brown adipose tissue (BAT). Sucrose feeding stimulated in vivo lipogenesis in BAT, white adipose tissue, and liver. Unilateral denervation reduced BAT norepinephrine content by 90%, and significantly reduced BAT protein and DNA content. Prior surgical denervation of BAT had no effect on lipogenesis in chow-fed rats, but reduced the sucrose-induced lipogenesis in BAT by 75% and increased lipogenesis in retroperitoneal white adipose tissue of sucrose-fed rats. These data demonstrate that the optimal stimulation of lipogenesis in BAT by sucrose feeding requires innervation of this tissue.

Dietary obesity in golden hamsters: Reversibility and effects of sex and photoperiod

Golden hamsters fed a high-fat diet do not overeat, but they become obese because of decreases in energy expenditure. This decrease in actual energy expenditure is accompanied by increases in thermogenic capacity and brown adipose tissue mass, protein content, and DNA content. Three experiments examined this phenomenon in more detail. Experiment 1 demonstrated that this form of dietary obesity is largely reversible simply by returning the animals to a high-carbohydrate chow diet. However, the obesity which develops solely because of decreased energy expenditure is reversed primarily by decreased energy intake. In this respect fat-fed hamsters resemble tube-fed rats. Experiment 2 revealed that the effects of high-fat diet are at least as robust in female hamsters as in males. Experiment 3 examined the interactions between diet and photoperiod. Short days (10 hr light per 24 hr) had almost no effect on male hamsters fed Purina chow. However, nearly all of the effects of the high-fat diet (i.e., increases in body weight gain, feed efficiency, carcass energy content, percent ingested energy stored in the carcass, carcass lipid content, brown adipose tissue protein, and brown adipose tissue DNA) were exaggerated in hamsters housed in short days. High-fat-diet-induced increases in metabolic efficiency and thermogenic capacity may be of value in readying hamsters for winter. Furthermore, as winter approaches, decreasing day length might synergize with changes in diet quality to promote these beneficial changes in energy metabolism. Finally, fat-fed hamsters could be a useful animal model of some kinds of human obesity.