Brown Fat Activity Research Articles

Metabolic and clinical consequences of changing from high-glucose to high-fat regimens in parenterally fed newborn infants

To evaluate the metabolic and clinical consequences of changing from high-glucose to high-fat regimens during initiation of parenteral nutrition, we performed 22 studies in 11 newborn infants (birth weight (mean +/- SD) 2.54 +/- 0.54 kg, gestational age 37 +/- 3 weeks, postnatal age 8 +/- 3 days) maintained in a constant thermal environment. In a paired design, two isoproteinic (2.4 +/- 0.2 gm/kg/day) and isocaloric (64 +/- 6 kcal/kg/day) regimens differing by source of energy (high glucose vs high lipid) were infused on consecutive days. Environmental and body temperatures were recorded during a 4-hour period, and 24-hour urinary excretions of catecholamines, nitrogen, and C peptide were measured. Despite constant incubator and average skin temperatures, the rectal and interscapular temperatures rose significantly when the high-glucose regimen was changed to a high-lipid regimen. The specific locations of these changes in body temperature suggested brown fat activation. A significant drop in nitrogen retention (63 +/- 9% vs 56 +/- 10%) during the lipid infusion could be further evidence of a metabolic adaptation to the rapid change in energy substrates.

Cold-induced changes in uncoupling protein and GDP binding sites in brown fat of ob/ob mice

The acute and chronic effects of cold exposure on the thermogenic activity and capacity of brown fat of obese (ob/ob) and lean mice have been examined. After 1 h at 13 degrees C, mitochondrial GDP binding increased in warm-acclimated (28 degrees C for 3 wk) lean mice, and increases in mitochondrial mass and the specific mitochondrial concentration of uncoupling protein were evident at 24 h. Long-term cold exposure led to further progressive increases in the specific mitochondrial concentration and total tissue content of uncoupling protein. The acute increase in GDP binding was due to an unmasking of binding sites on the protein and was accompanied by a parallel increase in the acetate-induced swelling of the mitochondria. In contrast to lean animals, ob/ob mice did not exhibit an increase in GDP binding or unmasking of binding sites during the first 24 h of cold exposure; unmasking was, however, evident by 3 days. A delay in the stimulation by cold of both the specific mitochondrial concentration of uncoupling protein (not increased until 3 days) and the mitochondrial content of brown fat (not increased until 8 days) occurred in the obese mice. Acute warm exposure (28 degrees C) of cold-acclimated (13 degrees C for 3 wk) mice led to a reduction in GDP binding in both lean and obese animals because of a rapid masking of binding sites. Mitochondrial content and the specific mitochondrial concentration of uncoupling protein fell progressively in both groups of mice with continued warm exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hypophysectomy on energy balance and brown fat activity in obese Zucker rats.

Hypophysectomy (HYPX) in genetically obese (fa/fa) Zucker rats significantly reduced body weight and energy gains and stimulated energy expenditure (by 34%), the thermic response to food (by 144%), and brown adipose tissue (BAT) mitochondrial GDP-binding capacity (by 190%) compared with pair-fed, sham-operated obese rats. These changes in energy balance in obese HYPX rats were reversed by corticosterone replacement (1 mg/day), but the increased BAT activity was only partly restored to normal. HYPX had only small effects on energy balance in lean Zucker rats compared with pair-fed, sham-operated lean controls but increased the acute thermic response to food and BAT mitochondrial GDP-binding capacity; these effects were inhibited by replacement of HYPX rats with corticosterone. The results suggest that alterations in the hypothalamic-pituitary-adrenal axis play a fundamental role in the development and maintenance of genetic obesity.

Cytochrome oxidase activity in brown fat varies with reproductive response and use of torpor in deer mice

Reproductive responses and thermogenic properties of brown adipose tissue (BAT) were evaluated in individuals from an outbred population of deer mice (Peromyscus maniculatus nebrascensis) after 10 weeks exposure to short photoperiod (8:16 light:dark) and cold ambient temperature (2°C). Deer mice populations are composed of phenotypes that differ in their reproductive response to environmental cues. These phenotypes also differ in body temperature regulation as indicated by their use of daily torpor. By comparing BAT responses among individuals of different phenotypes, we were able to assess the association between environmentally induced changes in reproduction and metabolism. Short/cold days caused increased proliferation of BAT and higher cytochrome oxidase activity. However, the magnitude of these changes varied with reproductive phenotype and use of daily torpor. BAT weight in short/cold day exposed males with normal sized testes more than doubled while total cytochrome oxidase activity increased by 30% as compared to controls. In contrast, short/cold day exposed deer mice with atrophic testes that employed daily torpor exhibited a 64% increase in BAT weight and 100% increase in total cytochrome oxidase activity, compared to control mice. Cytochrome oxidase activity in nontorpid deer mice with atrophic testes was intermediate to these two groups. Our results demonstrate a response of BAT to short/cold days that varies with individual reproductive response. This finding suggests that there exists a common integrative mechanism for temperature and photoperiod to regulate both seasonal reproductive and metabolic adjustments.

Influence of adrenalectomy on age-related changes in energy balance, thermogenesis and brown fat activity in the rat

1. 1. The effects of bilateral adrenalectomy (ADX) on energy balance, acute thermogenic responses to food and brown adipose tissue (BAT) thermogenic activity (mitochondrial GDP binding) were studied in rats adrenalectomized at 6 weeks of age (ADX-Y) or at 18 weeks of age (ADX-O). 2. 2. At 20 weeks of age, ADX-Y rats were lighter and exhibited higher levels of thermogenesis than intact controls. ADX-O rats also exhibited higher levels of thermogenesis compared with controls. 3. 3. The results suggest that the reduced thermogenesis that accompanies aging in the rat can be prevented by adrenalectomy at an early age, or reversed by adrenalectomy when much older.

Chronic inhibition of GABA transaminase results in activation of thermogenesis and brown fat in the rat

1. 1. Oral administration of the GABA transaminase inhibitor ethanolamine- O-sulphate (EOS, 5 mg/ml in drinking water) to rats for 14 days suppressed food intake by 24%, but reduced weight gain by over 35%. 2. 2. Thus, feed efficiency (g gain/MJ eaten) was decreased by over 15% in EOS-treated rats, suggesting that there had been an increase in metabolic rate. 3. 3. The thermogenic response (rise in oxygen consumption, VO 2) to injection of noradrenaline was enhanced by 50% and the thermogenic activity of brown adipose tissue (BAT, assessed from mitochondrial GDP-binding) was increased by 38% in EOS-treated rats. 4. 4. Injection of baclofen (a GABA B agonist, 0.5 mg/kg s.c.) stimulated VO 2 in both groups, with a significantly greater response in EOS treated rats, and this was enhanced by bicuculline (GABA A antagonist, 0.5 g/kg s.c.) in control rats and attenuated by muscimol (GABA A agonist, 0.5 mg/kg s.c.) in control and EOS-treated rats. 5. 5. The data indicate that increasing brain GABA concentrations with EOS results in lower levels of metabolic efficiency and increases in thermogenesis.

Oxygen supply and the placenta limit thermogenic responses in fetal sheep.

The aim of this study was to assess the individual effects of cooling, increased oxygenation, and umbilical cord occlusion on nonshivering thermogenesis in utero. A cooling coil was placed around eight fetal sheep of 132-145 days gestation; thermistors were placed in the fetal esophagus and maternal iliac artery, vascular catheters and a tracheal catheter were inserted, and a snare was placed loosely around the umbilical cord. The next day cold water was circulated through the coil for 5 h. During the 1st h of cooling alone, fetal core temperature fell 2.79 degrees C, but indexes of brown fat activity increased only slightly. After ventilation with O2, plasma free fatty acid concentration (FFA) rose 7.4-fold to 244 +/- 42 mu eq/l, glycerol concentration rose fourfold to 376 +/- 85 microM, and the difference between brown fat and core temperature widened to 0.60 +/- 0.10 degrees C. Ventilation with N2-enriched air did not evoke similar responses. After snaring the umbilical cord while ventilation was continued, FFA rose to 554 +/- 95 mu eq/l, glycerol rose to 684 +/- 76 microM, and the temperature difference widened to 0.77 +/- 0.13 degrees C. Whole-body O2 consumption peaked at 19.6 ml.min-1.kg-1 of fetal tissue. We conclude that fetal thermogenic responses are limited in part by O2 delivery to brown fat and are augmented by occlusion of the umbilical cord.

Influence of Carbohydrate and Fat Intake on Diet-Induced Thermogenesis and Brown Fat Activity in Rats Fed Low Protein Diets

Voluntary intake of protein, fat and carbohydrate (CHO) was modified by feeding young rats either a control purified diet [% metabolizable energy (ME): protein 21, fat 7, CHO 72], a control diet plus sucrose solution (20%) to drink (final intakes 17, 6 and 77% ME as protein, fat and CHO, respectively) or a low protein diet substituted with either CHO (8, 7 and 85% ME as protein, fat and CHO, respectively) or fat (8, 20 and 72% ME as protein, fat and CHO, respectively). Total ME intakes corrected for body size were similar for all rats, but body weight, energy gain and net energetic efficiency were lower in both low protein–fed groups than in the control group. The acute thermogenic response (% rise in oxygen consumption) to a standard balanced-nutrient meal was higher (12%) in sucrose-supplemented and in low protein groups (15-16%) than in control rats (8%). Brown adipose tissue protein content and thermogenic capacity (assessed from purine nucleotide binding to isolated mitochondria) were greater than control values in sucrose-fed and protein-deficient animals, and the greatest levels of activity were seen in low protein–fed rats with a high fat intake. The results demonstrate that the changes in energy balance, thermogenesis and brown adipose tissue activity that result from protein deficiency cannot be ascribed to changes in the level of energy intake or to a specific increase in the amount or proportion of either CHO or fat. They suggest that the protein-to-energy ratio must be the primary influence on thermogenesis and brown fat activity in these animals.

Changes in thermogenesis and brown fat activity in response to tumour necrosis factor in the rat.

A single intravenous injection of recombinant human tumour necrosis factor (TNF) resulted in significant, but transient (24-48 hr) reductions in food intake and body weight, and increases in rectal temperature, resting oxygen consumption (VO2) and brown adipose tissue (BAT) thermogenic activity (mitochondrial GDP-binding). The increased VO2 was inhibited by beta-adrenergic blockade (propranolol), and activation of BAT was prevented by denervation of the tissue. In adult (4-month old) animals, TNF induced greater reductions in food intake and body weight, caused general malaise and some fatalities, but did not significantly alter VO2 or BAT activity. However, the reduction in VO2 following beta-adrenergic blockade was greater in TNF-treated rats and BAT activity was enhanced when compared to pair-fed controls. Injection of adult rats with gamma-interferon induced small changes in body weight and temperature which were slightly potentiated when injected with a low dose of TNF. The results indicate that TNF stimulates sympathetic outflow to BAT. This effect may be partly responsible for the increases in body temperature and metabolic rate associated with TNF treatment and with cancer cachexia.

Body composition, food intake, and brown fat thermogenesis in pregnant Djungarian hamsters.

Strategies for balancing energy storage and expenditure during pregnancy were examined in the Djungarian hamster. In expt 1, pregnant hamsters lost nearly 50% of their body lipid stores, even though they showed significant increases in body weight and food intake during the latter half of pregnancy. The increase in body weight was accounted for by the growth of the uteri, fetuses, and placentas. The water and fat-free dry contents of the maternal carcasses did not differ from those of the unmated controls. In expt 2, brown fat cytochrome-c oxidase activity (mitochondrial content) was significantly lower in the late- but not early-pregnant females relative to the nonpregnant controls. Specific GDP-binding levels did not differ significantly among these groups. Thus an overall decrease in total thermogenic activity in brown fat would be expected during late pregnancy. The loss of carcass lipid, despite decreased brown fat thermogenesis and increased food intake, suggests that substantial increases in energy expenditure occur in pregnant females that are not related to heat production in brown fat. The present results are not consistent with traditional models of energy balance during pregnancy. Some of the inconsistencies may be related to differences between hoarding and nonhoarding families of rodents, whereas others may be due to the fact that the traditional model is based on a possibly exceptional species, the laboratory rat.

Effects of ciglitazone on energy balance, thermogenesis and brown fat activity in the rat

Young male rats were treated with vehicle or ciglitazone (150 mg/kg/day, intragastric) for 8 or 14 days. Drug treatment did not affect food intake but reduced body weight and energy gains over 14 days, and significantly depressed energetic efficiency. Energy expenditure and resting oxygen consumption (VO 2), when corrected for body size, were elevated in ciglitazone-treated rats, but the difference in VO 2 was abolished by treatment of the animals with a β-adrenergic antagonist (propranolol). The acute thermic response (postprandial rise in VO 2) to a fat meal was similar for both groups, but the response to carbohydrate ingestion was greater in ciglitazone-treated rats (18%) than controls (11.5%). The mass of interscapular brown adipose tissue was not affected by drug treatment, but its protein content was increased and its thermogenic activity (mitochondrial purine nucleotide binding) was elevated by 25% after chronic treatment with ciglitazone. These results indicate that ciglitazone enhances thermogenesis via sympathetic activation of brown adipose tissue, probably as a result of improved insulin sensitivity.

Effect of Environmental Temperature on Energy Balance and Thermogenesis in Rats Fed Normal or Low Protein Diets

Rats fed a low protein (9% metabolizable energy) diet and house at 24°C gained less weight and body energy then controls fed a normal (25%) protein diet. Energy intake and expenditure corrected for body size (kJ/(kg0.75·d)] were similar in rats fed the two diets, but energetic efficiency was suppressed in low protein-fed rats, and the thermogenic response to norepinephrine and the activity of brown adipose tissue (mitochondrial GDP binding) were both significantly elevated. Housing at a higher temperature (29°C) suppressed energy expenditure and brown fat activity in animals fed either diet, and gross efficiency was greater in control animals at 29°C than at 24°C but unaffected in the protein-deficient group. The differences in brown fat activity between dietary groups were still apparent at 29°C. The results suggest that thermogenesis induced by feeding low protein diets is not markedly inhibited by a higher environmental temperature.

Thermogenic activity and capacity of brown fat in fasted and refed golden hamsters.

The effects of different food deprivation regimens on the thermogenic activity and capacity of brown adipose tissue in the golden hamster have been investigated. Thermogenesis in the tissue was assessed by measurements of tissue cytochrome-c oxidase activity, mitochondrial GDP binding, and the specific mitochondrial concentration of uncoupling protein. The thermogenic activity and capacity of brown adipose tissue were found to be markedly reduced in fasted or underweight hamsters. Measurements of cytochrome-c oxidase activity indicate that the reductions were caused exclusively by a loss in mitochondrial mass, uncoupling protein concentration and GDP binding to mitochondria remaining unchanged. The decrease in brown adipose tissue thermogenesis was associated with a reduction in the capacity for nonshivering thermogenesis in the whole animal. Hamsters recovered from weight losses without increasing their food intake, and the recovery was accompanied by a normalization in mitochondrial mass in brown adipose tissue. Mitochondrial mass was, however, restored only after 10 days of ad libitum refeeding. These results suggest that the reduction in energy expenditure in the fasted hamster could relate to a decrease in brown adipose tissue thermogenesis, in addition to the previously reported decreases in resting metabolic rate and locomotor activity. Reductions in thermogenesis may also represent a further mechanism by which energy stores recover in the golden hamster without postfast hyperphagia.

Stimulation of S14 mRNA and lipogenesis in brown fat by hypothyroidism, cold exposure, and cafeteria feeding: evidence supporting a general role for S14 in lipogenesis and lipogenesis in the maintenance of thermogenesis.

In liver, thyroid hormone rapidly induces S14 mRNA, which encodes a small acidic protein. This sequence is abundantly expressed only in lipogenic tissues and is thought to have some function in fat metabolism. In the euthyroid rat, we measured 20-fold higher levels of S14 mRNA in interscapular brown adipose tissue than liver. Furthermore, whereas in liver or epididymal fat, hypothyroidism resulted in an 80% fall in S14 mRNA, in brown fat the level of this sequence increased a further 3-fold. In all three tissues, the expression of S14 mRNA correlated well with lipogenesis, as assessed by 3H2O incorporation. Physiological activation of brown fat by chronic cold exposure or cafeteria feeding increased the concentration of S14 mRNA in this tissue and again this was accompanied by a greater rate of fatty acid synthesis. Overall, in liver and white and brown adipose tissue, S14 mRNA and lipogenesis were well correlated and strongly suggest a function of the S14 protein related to fat synthesis. These studies suggest that the S14 protein and lipogenesis may be important for thyroid hormone-induced and brown adipose tissue thermogenesis and that stimulation of these functions in hypothyroid brown fat is a consequence of decreased thyroid hormone-induced thermogenesis elsewhere.

Stimulation of thermogenesis and brown fat activity in rats fed medium chain triglyceride

Gastric intubation of young male rats with 100 kJ/d of medium chain (C8 and C10) triglyceride (MCT) reduced their voluntary intake of stock diet such that total metabolizable energy intake was similar to that of rats intubated with water, and 41% of their energy intake was derived from MCT. Body weight, energy gain, and energetic efficiency were all markedly suppressed in MCT-fed rats, but energy expenditure over the 14-day experiment was significantly increased. Resting oxygen consumption, measured at thermoneutrality, was also enhanced in MCT-fed rats, but this difference was abolished by injection of the animals with the β-adrenergic antagonist, propranolol. Brown adipose tissue mass was similar for both groups, but the activity of the mitochondrial proton conductance pathway, assessed from the binding of purine nucleotides, was increased by over 70%. These data indicate that the reduced weight gains of animals fed MCT are due to elevated rates of energy expenditure, possibly resulting from sympathetic activation of brown fat thermogenesis.

Iodothyronine 5'-deiodinase activity in rat brown adipose tissue during development.

Iodothyronine 5'-deiodinase activity in rat brown adipose tissue has a characteristic pattern of developmental changes that is completely different from that of the liver. Fetal brown fat exhibits an extremely high iodothyronine 5'-deiodinase activity that is approx. 10-fold that in adult rats. Even though brown fat iodothyronine 5'-deiodinase activity falls suddenly at birth, there is a new peak in the activity around days 5-7 of life, whereas it remains very low afterwards. Just after birth, brown adipose tissue iodothyronine 5'-deiodinase activity is already capable of stimulation by noradrenaline. The postnatal peak in brown fat iodothyronine 5'-deiodinase correlates with the known increase in the thermogenic activity of the tissue in the neonatal rat, thus reinforcing the suggestion that local 3',3,5-triiodothyronine generation could be an important event related to thermogenesis in brown adipose tissue. However, the high fetal activity was only slightly related to the thermogenic activity of brown fat. Moreover, the increased iodothyronine 5'-deiodinase activity of brown adipose tissue during fetal and neonatal life suggests a substantial contribution by brown fat in the overall extrathyroidal 3',3,5-triiodothyronine production in these physiological periods.

Effects of Dehydroepiandrosterone Acetate on Metabolism, Body Weight and Composition of Male and Female Rats

Twenty adult Sprague-Dawley outbred rats (10 male and 10 female) were fed a nonpurified diet without or containing dehydroepiandosterone acetate (DHEA 6 g/kg diet) for 11 w. DHEA-treated animals weighed less than the controls after 6 wk and until the end of treatment. However, only the differences between male groups were statistically significant. Food intake of the DHEA-fed animals was not affected, but resting heat production was elevated for both sexes. Serum triglyceride levels and activity of hepatic glucose-6-phosphate dehydrogenase of the experimental groups were lower than controls. Analyses of body composition indicated DHEA-treated animals had proportionately less body fat and therefore more body water, protein and ash than controls. In most cases, differences in body composition were due primarily to effects of DHEA on the female animals. In a second experiment, DHEA treatment did not alter urinary ketone levels nor did it enhance citrate synthase activity in interscapular brown fat, skeletal muscle, heart or liver. Findings suggest that DHEA acetate treatment affected body weight, body composition and utilization of dietary energy by both impairing fat synthesis and promoting fat-free tissue deposition and resting heat production. Possible mechanisms by which DHEA may affect metabolism are discussed.

Impaired basal and noradrenaline-induced iodothyronine 5′-deiodinase activity in brown adipose tissue from pregnant and lactating rats

Basal iodothyronine 5'-deiodinase activity is lowered in brown fat from 20-day pregnant, 5 and 15-day lactating rats when compared with virgin controls. Acute noradrenaline treatment caused a seven fold increase in 5'-deiodinase activity in brown fat from virgin control rats. Late pregnant and lactating rats showed a reduction in noradrenaline-induced 5'-deiodinase activity in brown adipose tissue and the maximum impairment was observed in 15-day lactating rats. Lowered 5'-deiodinase activity in brown fat during late pregnancy and lactation correlates with the known reduction in the thermogenic activity of the tissue during these situations and agrees with the proposal that the rate of 3,5,3'-triiodothyronine generated in situ because of thyroxine 5'-deiodination could be an essential event related to thermogenesis in brown fat. Even though the relationship between 3,5,3'-triiodothyronine generation in the tissue and the specific thermogenic mechanisms of brown fat is unknown, present results indicate a close link between the thermogenic and 5'-deiodinase activities in physiological situations when brown adipose tissue needs to adapt to a low activity, such as that of the breeding cycle.

Capsaicin-induced changes in behavioural thermoregulation of newborn rabbits ( Lepus cuniculus)

1. 1.|An injection of capsaicin into normal young rabbits resulted in a preference for a cooler environment, signs of increased heat loss, and a suppression of the overall metabolic rate. 2. 2.|Body temperature declines with the preferred temperature, despite brown fat activation. 3. 3.|The response is greatly reduced after short-term desensitization, although the spontaneous motility, temperature selecting behaviour and body temperature appear to be normal.

Energy balance and brown fat activity in adrenalectomized male, female, and castrated male rats

Adrenalectomy (ADX) attenuated body weight and energy gains in male and female rats by inhibiting food intake and reducing energetic efficiency, and these changes were associated with marked increases in the thermogenic activity of brown adipose tissue (BAT). Feeding a palatable cafeteria diet to intact female rats stimulated energy intake, expenditure, and BAT activity and caused only small increases in body energy gain. Heat production in cafeteria-fed female rats was further enhanced by ADX. Castration in male rats had similar effects on energy balance and BAT to adrenalectomy, causing decreases in energy intake, expenditure, body energy gain, and energetic efficiency, but elevated BAT activity. Combined castration and ADX had synergistic effects resulting in marked increases in brown fat activity. These data indicate that male steroids may inhibit thermogenesis in a similar manner to the glucocorticoids, but the effects of adrenalectomy on energy balance are comparable in male and female rats.