Brown Adipose Tissue Sympathetic Activity Research Articles

Apolipoprotein A4 Elevates Sympathetic Activity and Thermogenesis in Male Mice.

Long-chain fatty acids induce apolipoprotein A4 (APOA4) production in the small intestine and activate brown adipose tissue (BAT) thermogenesis. The increase in BAT thermogenesis enhances triglyceride clearance and insulin sensitivity. Acute administration of recombinant APOA4 protein elevates BAT thermogenesis in chow-fed mice. However, the physiological role of continuous infusion of recombinant APOA4 protein in regulating sympathetic activity, thermogenesis, and lipid and glucose metabolism in low-fat-diet (LFD)-fed mice remained elusive. The hypothesis of this study was that continuous infusion of mouse APOA4 protein would increase sympathetic activity and thermogenesis in BAT and subcutaneous inguinal white adipose tissue (IWAT), attenuate plasma lipid levels, and improve glucose tolerance. To test this hypothesis, sympathetic activity, BAT temperature, energy expenditure, body weight, fat mass, caloric intake, glucose tolerance, and levels of BAT and IWAT thermogenic and lipolytic proteins, plasma lipids, and markers of fatty acid oxidation in the liver in mice with APOA4 or saline treatment were measured. Plasma APOA4 levels were elevated, BAT temperature and thermogenesis were upregulated, and plasma triglyceride (TG) levels were reduced, while body weight, fat mass, caloric intake, energy expenditure, and plasma cholesterol and leptin levels were comparable between APOA4- and saline-treated mice. Additionally, APOA4 infusion stimulated sympathetic activity in BAT and liver but not in IWAT. APOA4-treated mice had greater fatty acid oxidation but less TG content in the liver than saline-treated mice had. Plasma insulin in APOA4-treated mice was lower than that in saline-treated mice after a glucose challenge. In conclusion, continuous infusion of mouse APOA4 protein stimulated sympathetic activity in BAT and the liver, elevated BAT thermogenesis and hepatic fatty acid oxidation, and consequently attenuated levels of plasma and hepatic TG and plasma insulin without altering caloric intake, body weight gain and fat mass.

Nicotine exposure during breastfeeding reduces sympathetic activity in brown adipose tissue and increases in white adipose tissue in adult rats: Sex-related differences

Nicotine transfer via breast milk induces obesity in the adult offspring. We hypothesize that sympathetic nervous system (SNS) activity, brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) lipogenesis/adipogenesis are altered in adult rats that were exposed to nicotine exclusively during the breastfeeding period. Lactating Wistar rats were separated into two groups: nicotine (NIC), dams implanted with osmotic minipumps containing 6 mg/kg of nicotine at postnatal day (PN) 2; control, dams were implanted with saline-containing minipumps. Euthanasia occurred at PN120 or PN180. NIC offspring had lower BAT SNS activity and higher BAT lipid content. NIC males showed lower UCP1, β3-AR and CPT1a, while NIC females showed lower UCP1, TRα1, CPT1a, suggesting lower thermogenesis. NIC males showed higher WAT SNS activity, WAT β3-AR, adrenal catecholamine, FAS, PPARγ and adipocytes area, while NIC females showed higher ACC, FAS, CEBPβ and PPARγ. These findings indicate increased lipogenesis/adipogenesis in both sexes, with a possible compensatory sympathetic activated-lipolysis in males. NIC males had higher hypothalamic pAMPK/AMPK, explaining the lower BAT sympathetic activity. Neonatal nicotine exposure reduces BAT SNS activity and thermogenesis, and, only in males, increases WAT adipogenesis/lipogenesis, despite higher WAT SNS activity. These alterations can be associated with obesogenesis in this programming model.

Dopaminergic Projections to Raphe Pallidus Inhibit Brown Adipose Tissue Thermogenesis

BackgroundThe observations that patients with Parkinson's disease experience weight loss, while dopamine (DA) replacement therapy causes body weight gain, suggest that suppressing the DA system could stimulate energy expenditure. Peripheral administration of dopaminergic drugs decreases heat production by inhibition of brown adipose tissue (BAT) thermogenesis and by an increase in the threshold for muscular shivering. However, the exact neuroregulatory site through which DA modulates the activity of thermogenic thermoeffectors remains undefined.ResultsIn urethane/chloralose‐anesthetized, artificially‐ventilated rats, activation of type 2 or 3 dopamine receptors in the rostral raphe pallidus (rRPa) inhibits cold‐evoked BAT sympathetic activity, reduced BAT temperature and expired CO2, and produced hypotension and bradycardia. Anatomic evidence shows the co‐localization of TH and CTb immunoreactivities in neurons in the in the periventricular gray zona following injection of the retrograde tracer in the rRPa. These data indicate that this dopaminergic cell group projects to rRPa and is the likely source of the dopaminergic inhibition of BAT sympathetic activity.ConclusionOur data provide the first evidence that a DA input to the rRPa from periventricular gray zona modulates BAT thermogenesis and cardiovascular function. Modulating the dopaminergic input to rRPa could provide a novel therapeutic approach to promote fat oxidation, favor better glycaemic control, and accelerate weight loss.Support or Funding InformationNIH R01‐NS091066This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Neurons in the rat ventral lateral preoptic area are essential for the warm-evoked inhibition of brown adipose tissue and shivering thermogenesis.

To determine the role of neurons in the ventral part of the lateral preoptic area (vLPO) in CNS thermoregulation. In vivo electrophysiological and neuropharmacological were used toevaluate the contribution of neurons in the vLPO to the regulation of brown adipose tissue (BAT) thermogenesis and muscle shivering in urethane/chloralose-anaesthetized rats. Nanoinjections of NMDA targeting the medial preoptic area (MPA) and the vLPO suppressed the cold-evoked BAT sympathetic activity (SNA), reduced the BAT temperature (TBAT ), expired CO2 , mean arterial pressure (MAP), and heart rate. Inhibition of vLPO neurons with muscimol or AP5/CNQX elicited increases in BAT SNA, TBAT , tachycardia, and small elevations in MAP. The BAT thermogenesis evoked by AP5/CNQX in vLPO was inhibited by the activation of MPA neurons. The inhibition of BAT SNA by vLPO neurons does not require a GABAergic input to dorsomedial hypothalamus (DMH), but MPA provides a GABAergic input to DMH. The activation of vLPO neurons inhibits the BAT thermogenesis evoked by NMDA in the rostral raphe pallidus (rRPa), but not that after bicuculline in rRPa. The BAT thermogenesis elicited by vLPO inhibition is dependent on glutamatergic inputs to DMH and rRPa, but these excitatory inputs do not arise from MnPO neurons. The activation of neurons in the vLPO also inhibits cold- and prostaglandin-evoked muscle shivering, and vLPO inhibition is sufficient to evoke shivering. The vLPO contains neurons that are required for the warm ambient-evoked inhibition of muscle shivering and of BAT thermogenesis, mediated through a direct or indirect GABAergic input to rRPa from vLPO.

PPARγ activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1α and D2

Here, we investigated whether pharmacological PPARγ activation modulates key early events in brown adipose tissue (BAT) recruitment induced by acute cold exposure with the aim of unraveling the interrelationships between sympathetic and PPARγ signaling. Sprague-Dawley rats treated or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1), 7 days) were kept at 23°C or exposed to cold (5°C) for 24 h and evaluated for BAT gene expression, sympathetic activity, thyroid status, and adrenergic signaling. Rosiglitazone did not affect the reduction in body weight gain and the increase in feed efficiency, Vo(2), and BAT sympathetic activity induced by 24-h cold exposure. Rosiglitazone strongly attenuated the increase in serum total and free T4 and T3 levels and BAT iodothyronine deiodinase type 2 (D2) and PGC-1α mRNA levels and potentiated the reduction in BAT thyroid hormone receptor (THR) β mRNA levels induced by cold. Administration of T3 to rosiglitazone-treated rats exacerbated the cold-induced increase in energy expenditure but did not restore a proper activation of D2 and PGC-1α, nor further increased uncoupling protein 1 expression. Regarding adrenergic signaling, rosiglitazone did not affect the changes in BAT cAMP content and PKA activity induced by cold. Rosiglitazone alone or in combination with cold increased CREB binding to DNA, but it markedly reduced the expression of one of its major coactivators, CREB binding protein. In conclusion, pharmacological PPARγ activation impairs short-term cold elicitation of BAT adrenergic and thyroid signaling, which may result in abnormal tissue recruitment and thermogenic activity.

Sympathetic activation by fenfluramine depletes brown adipose tissue norepinephrine content in rats

The antiobesity agent fenfluramine (FEN) has been reported to produce an activation of sympathetic neurons to brown adipose tissue (BAT) resulting in thermogenesis. The present study was conducted to determine if FEN-induced activation of BAT is affected by the ambient temperature at which animals are maintained. Body temperature was determined in conscious male Sprague–Dawley rats using implanted temperature transmitters, and sympathetic activation of BAT was determined by measuring norepinephrine (NE) content. Animals maintained at 22 and 4 °C incurred a significant decline in core body temperature following FEN administration. FEN produced a significant depletion of BAT NE content, and the magnitude of BAT NE depletion was related to the dose of FEN (−57.4% at 3 mg/kg dose and −75.9% at 10 mg/kg dose). However, the extent of BAT NE depletion was equal at 22 and 4 °C. BAT NE depletion by FEN appears to depend on activation of sympathetic neurons because it was prevented by pretreatment with the ganglionic blocker pentolinium (10 mg/kg ip). Furthermore, NE depletion by FEN could be blocked with fluoxetine (10 mg/kg ip) pretreatment, indicating that the action of FEN is mediated through the release of serotonin.

Sympathetic activity in brown adipose tissue from rats adapted to a high protein, carbohydrate-free diet

Previous studies have shown that adaptation of rats to a high protein, carbohydrate-free (HP) diet results in a marked reduction in brown adipose tissue (BAT) thermogenic capacity. The present experiments were carried out to assess BAT sympathetic activity in HP diet-adapted rats. It was found that interscapular brown adipose tissue (IBAT) norepinephrine (NE) content, fractional turnover rate and calculated rate of turnover were markedly reduced in HP-fed rats. Replacement of the HP diet by a control, balanced diet for 24 h did not affect BAT NE content significantly, but restored fractional turnover rate and turnover rate values to those of control animals. Exposure to cold (4°) for a short period (8 h) induced a marked increase in IBAT NE fractional turnover rate and calculated turnover rate in both HP and control rats. The cold-induced rise of turnover rate over values at ambient temperature (25°C) was higher in HP rats than in controls. Rectal temperature after 8 h of cold exposure did not differ in HP and control rats. The data suggest that the decreased thermogenic capacity of rats adapted to a high protein, carbohydrate-free diet is due to a reduced sympathetic outflow to BAT, which can be rapidly reactivated by cold stimulation.

Involvement of sympathetic nervous system and brown fat in endotoxin-induced fever in rats.

The object of this study was to assess the role of brown adipose tissue (BAT) and the sympathetic nervous system in the rise in heat production associated with endotoxin-induced fever. Oxygen consumption (VO2) was found to be significantly increased (28%) over a 4-h period after two doses of endotoxin (Escherichia coli lipopolysaccharide, 0.3 mg/100 g body wt) given 24 h apart. Injection of a mixed beta-adrenoceptor antagonist (propranolol) reduced VO2 by 14% in endotoxin-treated rats, whereas the selective beta 1- (atenolol) or beta 2- (ICI 118551) antagonists suppressed VO2 by 10%. These drugs did not affect VO2 in control animals. BAT thermogenic activity assessed from measurements of in vitro mitochondrial guanosine 5'-diphosphate (GDP) binding was elevated by 54% in interscapular BAT and by 171% in other BAT depots. Surgical denervation of one lobe of the interscapular depot prevented these responses. Endotoxin failed to stimulate GDP binding in rats fed protein-deficient diets. This may have been because BAT thermogenic activity was already elevated in control rats fed these diets or because endotoxin caused a marked suppression of food intake in the protein-deficient animals. The results indicate that sympathetic activation of BAT is involved in the thermogenic responses to endotoxin and that these can be modified by dietary manipulation.

Dietary obesity: brown fat denervation fails to alter development or recovery.

We assessed the effect of scapular brown adipose tissue (BAT) denervation on dietary obesity in adult female Sprague-Dawley rats. In rats maintained for 32 days on an obesity-inducing regimen, BAT denervation produced significant reductions in food intake (83.4 vs. 94.4 kcal/day), weight gain (66.0 vs. 103.5 g), and carcass fat (19.3 vs. 27.6%). A subgroup of denervates consuming as many calories as controls (94.1 kcal/day) failed to gain more weight (92.2 g) or accumulate more fat (25.4%) than controls. In rats developing obesity for 32 days followed by 8 days on laboratory chow, weight change was unaffected by denervation during either weight gain (89.4 vs. 87.1 g for controls) or weight loss (21.2 vs. 22.1 g) phases, as was carcass fat (21.0 vs. 20.4%). BAT norepinephrine utilization was unchanged in nondenervated obese rats and those recovering from obesity. We did not, therefore, find evidence that under these experimental conditions sympathetic activation of BAT countered obesity during overconsumption or contributed to recovery from obesity.

Thermogenesis and sympathetic activity in BAT of overfed rats after adrenalectomy.

Resting oxygen consumption was elevated by 30% in young rats fed a cafeteria diet compared with their chow-fed controls and by 22% in cafeteria-fed, adrenalectomized (ADX) rats compared with the ADX chow-fed group, but injection of propranolol reduced oxygen consumption in the cafeteria-fed animals and abolished these differences. Brown adipose tissue (BAT) mass was increased by cafeteria feeding, and the activity of the mitochondrial proton conductance pathway (assessed from purine nucleotide binding) was enhanced by adrenalectomy and by cafeteria feeding. Norepinephrine turnover in BAT (determined from the time-dependent loss of tissue [3H]norepinephrine specific activity) was increased by 105% in sham-operated, cafeteria-fed rats, by 142% in chow-fed ADX rats, and by 400% in cafeteria-fed ADX rats, compared with chow-fed controls. Cardiac norepinephrine turnover was elevated by 80% in sham-operated, cafeteria-fed rats, but unaffected by adrenalectomy. These data indicate that the enhanced thermogenesis and BAT activity induced by adrenalectomy in chow- or cafeteria-fed rats is due to increased sympathetic activity in the tissue.

Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue of the rat.

Brown adipose tissue (BAT) is an important site of adaptive changes in thermogenesis in the rat. The sympathetic nervous system, which richly supplies BAT, is thought to play an important role in the regulation of BAT thermogenesis because catecholamines stimulate and beta adrenergic blocking agents inhibit oxygen consumption in this tissue. The present studies were carried out to assess directly sympathetic activity in BAT in response to cold exposure and to changes in dietary intake, both of which alter heat production in the rat. Sympathetic activity was determined from the rate of norepinephrine (NE) turnover in interscapular brown adipose tissue (IBAT) after preliminary experiments validated the use of NE turnover techniques in IBAT. Acute exposure to 4 degrees C increased NE turnover in IBAT 4- to 12-fold compared with ambient temperature controls, depending upon the interval over which the turnover measurement was made, while in the heart NE turnover doubled in response to the same cold stimulus. In animals exposed to cold continuously for 10 d before study, NE turnover measurements in IBAT and in the heart were elevated comparably to those obtained during acute exposure. Alterations in feeding were also associated with changes in NE turnover in IBAT. Fasting for 2 d decreased NE turnover in IBAT (-35% from 29.2+/-4.2 ng NE/h to 18.9+/-5.9) and in heart (-52%). In animals fed a "cafeteria" diet, a model of voluntary overfeeding in the rat, NE turnover was increased in both IBAT (+108% from 24.8+/-4.5 ng NE/h to 51.7+/-6.8) and heart (+66%). Because ganglionic blockade exerted a greater effect on NE turnover in IBAT in cafeteria-fed rats than in controls, the increase in NE turnover in IBAT with this overfeeding regimen reflects enhanced central sympathetic outflow. Thus NE turnover techniques can be satisfactorily applied to the assessment of sympathetic nervous system activity in IBAT. The experiments reported here demonstrate changes in sympathetic activity in IBAT that parallel known adaptive changes in heat production in the rat. These studies, therefore, support the concept that the increased thermogenesis of chronic cold exposure and of cafeteria feeding occur by similar mechanisms and imply an important role for the sympathetic nervous system, mediated in part through BAT, in the regulation of energy balance in the rat.

Impairment of trophic response of brown fat to cold in guanethidine-treated rats.

The aim of the present study was to investigate the role of the sympathetic nervous system in the trophic response of brown adipose tissue (BAT) to chronic cold exposure. The hyperplasia and the development of the mitochondria characterizing this response are usually considered as mainly controlled by the sympathetic activity in BAT, but this has never been clearly demonstrated. In the present work rats were sympathectomized by chronic administration of guanethidine and then exposed to cold during two weeks. The treatment induced a strong reduction of the noradrenaline content of BAT. The trophic response of the tissue to cold was largely impaired: no increase of the tissue weight, weak increase in the DNA, protein, and phospholipid content of the tissue. The development of the mitochondria was almost abolished. The increase in the proportion of the 32,000-dalton protein, a protein which regulates heat production by BAT, was suppressed and the GDP-binding to mitochondria, which is an index of BAT thermogenic capacity, was not increased as in normal cold-adapted rats. The ultrastructure of the tissue remained the same as in warm-adapted animals. It is concluded that the sympathetic nervous system plays an essential role in the control of the trophic response of BAT to the cold.