Control Of Non-shivering Thermogenesis Research Articles

Regulation of adiposity by mTORC1.

ABSTRACTObesity is characterized by an excessive increase in the adipose tissue mass, and is associated with higher incidence of several chronic metabolic diseases, such as type 2 diabetes. Therefore, its increasing prevalence is a public health concern, and it is important to better understand its etiology to develop new therapeutic strategies. Evidence accumulated over the years indicates that obesity is associated with a marked activation in adipose tissue of the mechanistic target of rapamycin complex 1 (mTORC1), a signaling pathway that controls lipid metabolism, and adipocyte formation and maintenance. Curiously, mTORC1 is also involved in the control of nonshivering thermogenesis and recruitment as well as browning of white adipose tissue. In this review, we explored mTORC1 functions in adipocytes and presented evidence, suggesting that mTORC1 may either increase or reduce adiposity, depending on the conditions and activation levels.

Deletion of Inducible Nitric-Oxide Synthase in Leptin-Deficient Mice Improves Brown Adipose Tissue Function

BackgroundLeptin and nitric oxide (NO) on their own participate in the control of non-shivering thermogenesis. However, the functional interplay between both factors in this process has not been explored so far. Therefore, the aim of the present study was to analyze the impact of the absence of the inducible NO synthase (iNOS) gene in the regulation of energy balance in ob/ob mice.Methods and FindingsDouble knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated, and the expression of molecules involved in the control of brown fat cell function was analyzed by real-time PCR, western-blot and immunohistochemistry. Twelve week-old DBKO mice exhibited reduced body weight (p<0.05), decreased amounts of total fat pads (p<0.05), lower food efficiency rates (p<0.05) and higher rectal temperature (p<0.05) than ob/ob mice. Ablation of iNOS also improved the carbohydrate and lipid metabolism of ob/ob mice. DBKO showed a marked reduction in the size of brown adipocytes compared to ob/ob mutants. In this sense, in comparison to ob/ob mice, DBKO rodents showed an increase in the expression of PR domain containing 16 (Prdm16), a transcriptional regulator of brown adipogenesis. Moreover, iNOS deletion enhanced the expression of mitochondria-related proteins, such as peroxisome proliferator-activated receptor γ coactivator-1 α (Pgc-1α), sirtuin-1 (Sirt-1) and sirtuin-3 (Sirt-3). Accordingly, mitochondrial uncoupling proteins 1 and 3 (Ucp-1 and Ucp-3) were upregulated in brown adipose tissue (BAT) of DBKO mice as compared to ob/ob rodents.ConclusionAblation of iNOS improved the energy balance of ob/ob mice by decreasing food efficiency through an increase in thermogenesis. These effects may be mediated, in part, through the recovery of the BAT phenotype and brown fat cell function improvement.

The caudal periaqueductal gray participates in the activation of brown adipose tissue in rats

To investigate the involvement of the periaqueductal gray (PAG) in the control of non-shivering thermogenesis, we tested the effects of electrical or chemical stimulation of the PAG on thermogenesis of brown adipose tissue (BAT) in urethane anesthetized rats. Electrical stimulation (0.1 mA, 33 Hz, 0.5 ms) or application of d, l-homocysteic acid (0.5 mM, 0.3 μl) into the lateral region of the caudal PAG (cPAG) elicited BAT thermogenesis, measured as a rise in the local temperature of interscapular BAT. These results suggest that neurons in the cPAG send excitatory efferent signals for BAT thermogenesis.

Efferent projection from the midbrain periaqueductal gray matter for the control of non-shivering thermogenesis in rats

Efferent projection from the midbrain periaqueductal gray matter for the control of non-shivering thermogenesis in rats

Potential defect in the vascular control of nonshivering thermogenesis in the obese Zucker rat hind limb

Vascular control of nonshivering thermogenesis in the perfused hind limb of obese and lean Zucker rats were compared using two vasoconstrictors, norepinephrine and serotonin. For hind limbs of both phenotypes, norepinephrine infusions resulted in a dose-dependent uninterrupted increase in perfusion pressure and a biphasic change in oxygen uptake (VO2), characterized by a stimulation at low concentrations, and an increasing inhibition at higher concentrations that gradually overcame the stimulation in a dose-dependent manner. At concentrations of norepinephrine greater than 1 microM, the inhibitory effect predominated and gave rise to values for VO2 less than basal. The obese hind limb had a lower basal VO2 and a lower maximal VO2 mediated by norepinephrine than the lean rat, but these differences appeared to relate largely to the lower muscle mass and higher content of fat of the obese hind limb. Serotonin infusions resulted in dose-dependent increase in perfusion pressure and an accompanying decrease in VO2. Pressure changes were identical for the obese and lean hind limbs, but the decrease in VO2 due to serotonin was greater in the hind limbs from the lean rats, and this difference remained when the data were expressed in terms of muscle mass perfused. It is concluded that the relatively lower content of muscle of the obese hind limb accounts for its lower basal and lower maximal norepinephrine-mediated thermogenesis. In addition, an intrinsic defect in obese hind limb muscle response to serotonin is present, which may be indicative of a decrease in the potential for vasoconstrictor-regulated thermogenesis that could have implications for whole-body energy balance by the obese phenotype.

Non-shivering thermogenesis during prostaglandin E 1 fever in rats: role of the cerebral cortex

We have tested the hypothesis that there is a role for the cerebral cortex in the control of non-shivering thermogenesis during fever induced by prostaglandin E 1 (PGE 1). While under urethan anesthesia, the firing rate of nerves innervating interscapular brown adipose tissue (IBAT), IBAT and colonic temperatures ( T IBAT and T c) and oxygen (O 2) consumption were monitored during the fever from PGE 1 injection (400 and 800 ng) in a lateral cerebral ventricle in controls and in functionally decorticated Sprague-Dawley rats. Rats were functionally decorticated by applying 3.3 M KCl solution on the frontal cortex which causes cortical spreading depression (CSD). Pyrogen injections caused dose-related increases in firing rate, T IBAT, T c and O 2 consumption and CSD reduced these enhancements. Our findings indicate that the cerebral cortex could be involved in the control of non-shivering thermogenesis during PGE 1-induced febrile response.

Thermosensitivity of the preoptic region and the spinal cord in the golden hamster

1. 1.|The effects of thermal stimulation of the preoptic region (POAH) and the spinal cord on non-shivering thermogenesis (NST) and shivering were studied in euthermic golden hamsters. 2. 2.|Shivering intensity is suppressed by heating the POAH but is independent of spinal cord temperature. Therefore, NST in the interscapular brown adipose tissue does not suppress shivering. 3. 3.|NST is inhibited by heating of the POAH as well as of spinal cord. It is discussed that the control of NST by two different central thermosensitive areas is significant for thermoregulation during exercise.

Effect of the adrenocorticostatic agent, metopirone, on thermoregulatory heat production in the European hedgehog*.

1. Non-shivering thermogenesis (NST) was studied in 8 hedgehogs before and after a single injection of metopirone ditartrate (150-450 mg/kg, i.p.) at a thermoneutral chamber temperature (Ta) of 28C and during cold exposure (Ta = 8 degrees C for 20 min). 2. An average metabolic increase of 149% of the standard metabolic rate (SMR) was observed 12-26 min after an injection of metopirone ditartrate at thermoneutral chamber temperature. Average temperatures simultaneously increased by 2.1C in the brown adipose tissue (BAT) and 2.0C in the deep colon. This initial effect lasted for 40 plus or minus 8 min. 3. In a period of 3-48 h after injection of metopirone ditartrate, cold-induced NST was reduced by 89% of SMR (av.). Concomitant exposure to cold caused average temperatures to decrease by 1.0C in the BAT and 1.1 C in the colon relative to control experiments. 4. Our results suggest the participation of corticosteroids in the control of NST in the hedgehog. As metopirone blocks enzymatic 11 beta-hydroxylation in the steroid ring, there is a pronounced increase of endogenous 11-deoxycorticosteroids, such as deoxycorticoterone (DOC). An injection of DOC (3 mg/kg, i.m.) increases NST at hermoneutrality similar to the initial metabolic effect elicited by metopirone ditartrate. The reduced response to cold exposure after several hours may be explained by competitive inhibition of glucocorticoid receptors since there is also an increased production of other 11-deoxycorticosteroids.

Interaction of superficial and hypothalamic thermosensitive structures in the control of non-shivering thermogenesis.

Previous studies (Briick and Wiinnenberg, 1967a, b; 1970) showed that in the guinea pig shivering is controlled by at least two sets of thermal receptors, one being located in the body surface, the other in the cervical spinal cord, and that there occurs "multiplicative" evaluation of the temperature signals. Further, hypothalamus temperature did not seem to have any influence on shivering; however, it did influence non-shivering thermogenesis (NST); here, the question arose if "multiplicative control" could be demonstrated in the NST~control system as well. Thus we carried out a series of studies with the aim of describing NST quantitatively as a function of body surface and central temperatures.