Lateral and medial hypothalamic lesions do not acutely affect brown adipose tissue thermogenesis

The acute effect of lateral (LH) and medial (MH) hypothalamic lesions on mitochondrial GDP binding in brown adipose tissue (BAT) (an index of thermogenic state) was studied one and two days postlesion. Groups of rats were lesioned, sham-lesioned, or unoperated and were all fasting. An additional group of unoperated rats had access to food throughout the study. The objective was to determine whether the hypermetabolic state and rapid weight loss known to be induced by LH lesions were attributable to the activation of BAT thermogenesis, and, if so, whether these effects were specific for LH lesions. No effect of either lesion on BAT thermogenic state could be detected at either time studied. Despite that fact, LH-lesioned rats, but not MH-lesioned rats, were hyperthermic at both times. We conclude that the prolonged hyperthermia which occurs shortly after LH lesions is not due to an activation of BAT thermogenesis. Instead, it can be likened to the febrile state in which an initial and brief activation of both nonshivering thermogenesis in BAT and shivering thermogenesis in muscles occurs only during the rising phase of the fever and is suppressed as soon as a stable hyperthermic state is reached. It thus appears unlikely that substantial and prolonged activation of BAT thermogenesis is a major mechanism that promotes exaggerated short-term weight loss in the LH-lesioned rat.     

Pontine and basal forebrain transections disinhibit brown fat thermogenesis in neonatal rats

Bignall, Heggeness and Palmer (1975) were the first to demonstrate increases in metabolic heat production following midpontine transection in neonatal rats. Subsequent work in adult rats has shown that this procedure disinhibits thermogenesis by brown adipose tissue (BAT). Bignall and his colleagues also found that hypothalamic ablation did not result in increased thermogenesis in 5-day-olds, leading them to conclude that thermoregulation depends on more caudal structures at that age. We have also found that midpontine transection disinhibits BAT thermogenesis and, furthermore, have extended that finding to newborn pups. When transections were made in the basal forebrain, however, we also found profound and rapid increases in brown fat thermogenesis. These results suggest the presence of at least two sources of inhibition of BAT thermogenesis in newborn rats: one located in the rostral pons-caudal midbrain and one located in the basal forebrain.     

Impaired diet-induced thermogenesis in brown adipose tissue from rats made obese with parasagittal hypothalamic knife-cuts

Two experiments were performed to determine if bilateral parasagittal hypothalamic knife-cuts (KCs), which produce long-term overeating and obesity, after biochemical indices of brown adipose tissue (BAT) reactivity to thermogenic stimuli. In the first study, responses to environmental cold were tested. Four weeks after surgery, KC rats had gained 4-5 times more weight than controls and were obese (increased Lee Obesity Index and weight of gonadal white fat). Before being sacrificed, groups of KC and control rats were exposed to 4 degrees C for 21 hr or remained at 28 degrees C. Interscapular BAT weighed 300% more in KC rats, due largely to increased white fat content. Functional indices of BAT thermogenic capacity (protein content, DNA content, cytochrome oxidase activity and mitochondrial guanosine diphosphate (GDP) binding) were normal at 28 degrees C. Exposure to 4 degrees C produced greatly enhanced responses but these were equivalent for both groups. This suggested an intact capacity for non-shivering thermogenesis in obese KC rats. In the second study, the same BAT responses were examined in other rats fed a palatable "cafeteria" diet (CAFE). One week after surgery, KC and control rats were subdivided into groups that received chow alone or chow plus four different palatable foods daily. Before sacrificing 4-5 weeks later, KC rats had gained 3-4 times more weight than controls and were obese. Interscapular BAT weighed 200-300% more in KC rats. CAFE feeding produced larger increments in all variables for KC vs. control rats. Most importantly, GDP binding was reduced in both KC groups, and significantly more so after CAFE feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurons of the rat preoptic area and the raphe pallidus nucleus innervating the brown adipose tissue express the prostaglandin E receptor subtype EP3

The major effector organ for thermogenesis during inflammation or experimental pyrogen-induced fever in rodents is the brown adipose tissue (BAT). Prostaglandin E2 (PGE2) microinjection into the medial preoptic area (POA) of rats leads to hyperthermia through an increase in BAT thermogenesis and induces pyrogenic signal transmission towards the raphe pallidus nucleus (RPa), a brainstem nucleus known to contain sympathetic premotor neurons for BAT control. The medial POA has a high expression of prostaglandin E receptor subtype EP3 (EP3R) on POA neurons, suggesting that these EP3R are main central targets of PGE2 to mediate BAT thermogenesis. To reveal central command neurons that contain EP3R and polysynaptically project to the BAT, we combined EP3R immunohistochemistry with the detection of transneuronally labelled neurons that were infected after injection of pseudorabies virus into the BAT. Neurons double-labelled with EP3R and viral surface antigens were particularly numerous in two brain regions, the medial POA and the RPa. Of all medial POA neurons that became virally infected 71 h after BAT inoculation, about 40% expressed the EP3R. This subpopulation of POA neurons is the origin of a complete neuronal chain that connects potential PGE2-sensitive POA neurons with the BAT. As for the efferent pathway of pyrogenic signal transmission, we hypothesize that neurons of this subpopulation of EP3R expressing POA neurons convey their pyrogenic signals towards the BAT via the RPa. We additionally observed that two-thirds of those RPa neurons that polysynaptically project to the interscapular BAT also expressed the EP3R, suggesting that RPa neurons themselves might possess prostaglandin sensitivity that is able to modulate BAT thermogenesis under febrile conditions.     

Brown (BAT) and white (WAT) adipose tissue in high-fat junk food (HFJF) and chow-fed rats with dorsomedial hypothalamic lesions (DMNL rats)

Male weanling rats received dorsomedial hypothalamic nucleus lesions (DMNL) or sham operations and were fed for 173 postoperative days a high-fat diet and given a 32% sucrose solution as drinking fluid. This was supplemented with chocolate chip cookies, potato chips and marshmallows. Other DMNL and sham-operated controls were fed lab chow instead of the above high-fat junk food diet (HFJF) and given tap water instead of 32% sucrose solution. All animals were killed on postoperative day 174. Caloric intake per 100 g body weight was similar in all groups; however, the HFJF fed control and DMNL rats had significantly elevated carcass fat. Since HFJF-DMNL rats were not nearly as obese as the HFJF control animals, it appears that the DMNL offered some protection against the HFJF-diet-produced obesity. When their smaller body size is considered. DMN lesions had no effect on brown adipose tissue (BAT) mass in chow-fed or HFJF fed rats, whereas BAT size was significantly enlarged in HFJF-fed control animals. This suggests but does not prove that HFJF-fed controls, but not DMNL rats, may be using dietary-induced thermogenesis (DIT) to attenuate their obesity. We hypothesize that the HFJF-fed DMNL may not be enhancing DIT as reflected in normal BAT size, because they had not attained a degree of fatness to activate this system, or the DMN lesions impaired its activation. Both HFJF-fed groups showed reduced linear growth compared to their counterparts. The reason for stunting is uncertain, but may be related to their low plasma insulin concentrations.     

An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis

Orexin (hypocretin) neurons, located exclusively in the PeF-LH, which includes the perifornical area (PeF), the lateral hypothalamus (LH), and lateral portions of the medial hypothalamus, have widespread projections and influence many physiological functions, including the autonomic regulation of body temperature and energy metabolism. Narcolepsy is characterized by the loss of orexin neurons and by disrupted sleep, but also by dysregulation of body temperature and by a strong tendency for obesity. Heat production (thermogenesis) in brown adipose tissue (BAT) contributes to the maintenance of body temperature and, through energy consumption, to body weight regulation. We identified a neural substrate for the influence of orexin neurons on BAT thermogenesis in rat. Nanoinjection of orexin-A (12 pmol) into the rostral raphe pallidus (rRPa), the site of BAT sympathetic premotor neurons, produced large, sustained increases in BAT sympathetic outflow and in BAT thermogenesis. Activation of neurons in the PeF-LH also enhanced BAT thermogenesis over a long time course. Combining viral retrograde tracing from BAT, or cholera toxin subunit b tracing from rRPa, with orexin immunohistochemistry revealed synaptic connections to BAT from orexin neurons in PeF-LH and from rRPa neurons with closely apposed, varicose orexin fibers, as well as a direct, orexinergic projection from PeF-LH to rRPa. These results indicate a potent modulation of BAT thermogenesis by orexin released from the terminals of orexin neurons in PeF-LH directly into the rRPa and provide a potential mechanism contributing to the disrupted regulation of body temperature and energy metabolism in the absence of orexin.     

Hypothalamus and Brown Fat: White and Brown Adipose Tissue Lipolysis in Weanling Rats with Dorsomedial Hypothalamic Lesions

Weanling male Sprague-Dawley rats received bilateral electrolytic lesions in the dorsomedial hypothalamic nuclei (DMN); sham-operated animals served as controls. The animals were fed lab chow and given tap water ad libitum. Fourteen days after the hypothalamic operation they were weighed and measured to assess ponderal and linear growth gains and Lee Index and were sacrificed on the following day. Body weight, body weight gain over two weeks, nose-tail length and gain in nose-tail length, and food intake were all highly significantly reduced in DMNL rats in comparison with controls. Lee Index and efficiency of food utilization were normal, however. Epididymal fat pads weighed less in both absolute and relative (percentage body weight) terms than in controls. Basal lipolysis was increased and epinephrine-stimulated lipolysis was decreased in DMNL rats, as was the protein content of the epididymal fat pads. Lipid content was normal, however. Interscapular brown adipose tissue (BAT) was significantly lighter in DMNL rats than in controls in absolute terms, but all other parameters measured were normal, as were plasma glucose, glycerol, and free fatty acids. Comparison with results from rats that received ventromedial hypothalamic lesions shortly after weaning indicates a differential effect in most epididymal fat pad parameters but similarities to changes in BAT. These data add to previous demonstrations of normal responses to homeostatic challenges in the growth-retarded, hypophagic-hypodipsic rat with lesions in the dorsomedial hypothalamic nucleus.     

Brown adipose tissue thermogenesis induced by low level electrical stimulation of hypothalamus in rats

Brown adipose tissue (BAT) is an energy dissipating form of adipose tissue implicated in non-shivering thermogenesis as well as diet-induced thermogenesis. In the present study, in vivo interscapular BAT (IBAT) temperature was recorded prior to and following low level electrical stimulation (a 30 sec train of 60 Hz, 100 microA 0.5 msec isolated pulses) of various hypothalamic regions in rats. Significant increases in IBAT temperature were observed after stimulation of the anterior, medial preoptic, paraventricular and dorsomedial hypothalamus but not after stimulation of either ventromedial or caudal hypothalamus. For positive sites, IBAT temperature typically increased at 3-4 minutes following stimulation, peaked at 7-8 minutes after stimulation and declined at 20 minutes after stimulation. Although alterations in diet-induced thermogenesis have been reported after ventromedial hypothalamic lesions, the increases in BAT temperature noted in the present study suggest that inhibitory fibers that course through the paraventricular hypothalamus may form part of the central nervous system control of brown adipose tissue thermogenesis induced by overfeeding.     

Consummatory, anxiety-related and metabolic adaptations in female rats with alternating access to preferred food

Avoidance of and relapse to palatable foods is a qualitative aspect of dieting, a putative risk factor for eating disorders or obesity. The present studies tested the hypotheses that rats with alternating access to highly preferred foods would show: (1) hypophagia, a function of the relative hedonic value of the underaccepted diet, (2) increased anxiety-like behavior and psychomotor arousal when preferred diet was unavailable, (3) obesity-like changes, and (4) stable individual differences in diet-switch-induced hypophagia. Preferences among three high-carbohydrate diets were determined in female Wistar rats (n=16). Adolescent rats (n=162) received the following weekly diet schedules: (1) continuous regular chow (7 days/week), (2) chow (5 days/week) followed by a more preferred diet (2 days/week), or (3) chow (5 days/week) followed by a less preferred chow (2 days/week). Some animals were yoke-restricted (75% calories) when provided chow to increase its rewarding properties. Diurnal locomotor activity was measured in a familiar environment, and anxiety-like behavior was assessed in the elevated plus-maze and defensive withdrawal tests. Rats withdrawn from the preferred diet showed hypophagia, anxiogenic-like behavior, increased locomotion, and weight loss. Chow hypophagia was progressive, individual-specific in magnitude, (partly) non-homeostatic in nature, and blunted by previous chow restriction. Despite eating less, rats cycled with the preferred diet became heavier, fatter, and diurnally less active, with greater feed efficiency and proinflammatory adipokine levels than chow controls. The present diet cycling procedure may model consummatory, anxiety-related, and metabolic effects of qualitative dieting in humans.     

Comparison of deficits in electrical self-stimulation after ibotenic acid lesion of the lateral hypothalamus and the medial prefrontal cortex

The aim of the present study was to compare the self-stimulation deficit produced by a unilateral injection of the neurotoxin, ibotenic acid, in the lateral hypothalamus (LH) to the deficit produced by the same unilateral injection in the medial prefrontal cortex (MPC). Four groups of adult male Sprague-Dawley rats were used: in two control groups, electrodes were bilaterally implanted in the LH (5 rats) or in the MPC (6 rats) and self-stimulation (ICSS) was obtained separately with the right and left electrodes. In the two experimental groups the intrinsic neurons of the LH (8 rats) or of the MPC (10 rats) were destroyed unilaterally by local injection of ibotenic acid (4 micrograms in 0.5 microliter); the other side served as the sham-lesioned control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral region. As in the case of the control rats, ICSS was determined separately for each electrode, first by a rate dependent test (nose-poke) then by a 'rate-free' test (shuttle-box). In the LH and MPC control rats, ICSS responses were the same with stimulation on either side. In the LH-lesioned rats, the ICSS rates measured with the nose-poke test were significantly decreased with stimulation on the lesioned side, whereas rates with stimulation of the non-lesioned LH were normal. Likewise, while shuttle responses with stimulation of the non-lesioned LH were normal, the OFF-time was increased and the ON-time was decreased with stimulation of the lesioned LH. In the MPC-lesioned rats, ICSS (nose-poke) was totally suppressed and the shuttle responses were disorganized since neither the ON- nor the OFF-times changed in response to increasing current intensities. Nose-poke responses with stimulation of the non-lesioned MPC were just about normal. These results show that in the two brain regions studied local neurons are involved in ICSS. The difference in the magnitude of the deficit observed suggests, that the neuronal circuits involved in MPC self-stimulation are poorly represented whereas in the LH many neuronal circuits involved in these mechanisms overlap.     

Glutamate injection into the suprachiasmatic nucleus stimulates brown fat thermogenesis in the rat

Injection of glutamate (100 mM to 1 M, in 0.25 μl saline) into the hypothalamic suprachiasmatic nucleus (SCN) dose-dependently increased interscapular brown adipose tissue (IBAT) and core temperatures in the urethane-anaesthetized rat. This effect was more pronounced in rats tested during the light-off period than in animals tested during the light-on period. Prior injection of the local anaesthetic, procaine (5% in 0.5 μl saline), into the ipsilateral ventromedial hypothalamic nucleus (VMH) attenuated the increases in IBAT and core temperatures induced by intra-SCN glutamate. The VMH has previously been implicated in the central regulation of BAT thermogenesis; the present results suggest the pathway arising in the SCN exerts an excitatory influence on VMH neurons involved in the control of BAT function.     

Nonshivering thermogenesis

Nonshivering thermogenesis was originally defined as a cold-induced increase in heat production not associated with the muscle activity of shivering. Recent research shows it to be a metabolic process located primarily in brown adipose tissue and controlled by the activity of the sympathetic nervous supply of this tissue. Another stimulus to sympathetic nervous activity, the ingestion of food, promotes diet-induced thermogenesis in brown adipose tissue. Brown adipose tissue grows and regresses in accordance with the extent to which it is stimulated, either by cold or by diet, and the capacity of the animal for cold-induced nonshivering thermogenesis and diet-induced thermogenesis increases or decreases accordingly. In certain hibernators another stimulus, photoperiod, promotes growth or regression of brown adipose tissue. The neural regulation of thermogenesis in brown adipose tissue is thus not only part of the central control mechanisms involved in thermoregulation but also part of those involved in the regulation of energy balance. In hibernators , such as the hamster, the neural regulation of thermogenesis in brown adipose tissue includes, in addition, central components that control the function of brown adipose tissue during entry into and arousal from hibernation and pineal or melatonin-related components that control its growth in response to photoperiod. In animals which become intermittently torpid, such as the mouse, the regulation includes in addition central components that control the function of brown adipose tissue during entry into and arousal from torpor. The central neural components involved in control of thermoregulation are better understood than are those involved in the regulation of energy balance. Studies of animal with hypothalamic obesity indicate that the control of diet-induced thermogenesis in brown adipose tissue requires the participation of the ventromedial region of the hypothalamus whereas the control of cold-induced nonshivering thermogenesis does not. The importance of comparative studies in different species is emphasized since any neural model for the control of brown adipose tissue thermogenesis is likely to apply in detail only to the species for which it was developed.     

Involvement of the raphé pallidus in the suppressive effect of preoptic warming on non-shivering thermogenesis in rats

Thermogenesis in the brown adipose tissue (BAT) is activated by the stimulation of the ventromedial hypothalamic nucleus (VMH). Local warming of the preoptic area (PO) suppresses this response. Injection of the GABA(A) receptor antagonist bicuculline into the caudal periaqueductal gray (cPAG), where excitatory neurons for BAT thermogenesis are located, did not influence the suppressive effect of PO warming. On the other hand, after bicuculline injection into the raphé pallidus, where excitatory neurons for BAT thermogenesis are also located, VMH stimulation produced BAT thermogenesis even during PO warming. The present results suggest that the inhibitory signal from the PO reaches the raphé pallidus and not the cPAG for the control of BAT thermogenesis.     

Insulin co-injection suppresses the thermogenic response to glutamate microinjection into the VMH in rats

Selective stimulation of ventromedial hypothalamic nucleus (VMH) neurons by microinjection of the excitatory amino acid glutamate sharply increased interscapular brown adipose tissue (IBAT) and core temperatures in urethane-anaesthetized rats. This effect was blocked by co-injection of insulin (0.1-1 microgram) though not an inactive insulin analog, TNB3 insulin. Injection of insulin (1 microgram) into the contralateral VMH or systemic administration of insulin (1 microgram) had no effect on the thermogenic response to intra-VMH glutamate. These results complement those showing that intra-VMH insulin suppresses the basal firing rate of sympathetic nerves to IBAT and diminishes cold-induced nonshivering thermogenesis in BAT and add support to the view that insulin functions as an inhibitory signal on VMH neurons controlling thermogenesis in BAT.     

Hyperthermia induced by pre-pontine knife-cut: Evidence for a tonic inhibition of non-shivering thermogenesis in anaesthetized rat

Temperature of colon, interscapular brown adipose tissue (IBAT) and paw skin (index of vasomotor activity) were monitored before and after microwire knife lesions at the pre-pontine or/and the post-mammilary levels in the urethane-anaesthetized rats at room temperature of 23–24°C. Following the pre-pontine, but not the post-mammilary cut, colonic and IBAT temperatures increased by 3–4°C within 90–240 min. IBAT temperature rose faster with a shorter latency and attained a higher steady-state value than colonic temperature; skin temperature, however rose by only 0.8°C. A procaine microinjection into the pre-pontine area transiently increased by more than 1°C both colonic and IBAT temperatures, with similar kinetic as for the knife cut. Cardiac output distribution was measured using radiolabelled microspheres. Brown adipose tissue (BAT) was found to be the only organ to which the fractional blood flow increased dramatically (12 times over baseline value) during the development of hyperthermia. Propranolol, injected after the hyperthermia had fully developed, decreased IBAT and then colonic temperatures. Hexamethonium decreased both colonic and IBAT temperatures with a concomitant rise in skin temperature while tubocurarine was without effect. It is concluded that the hyperthermia observed after the pre-pontine lesion results from an increased sympathetic stimulation of BAT thermogenesis triggered by the release of a tonic inhibitory control on its heat production. Such an inhibitory system would be located somewhere between the lower midbrain and the upper pons.     

Difference in brown adipose tissue effector response and associated thermoresponsiveness of ventromedial hypothalamic (VMH) neurons of 21°C vs. 4°C acclimatized rats to scrotal thermal stimulation

The present study was designed (1) to determine if scrotal thermal stimulation would activate brown adipose tissue (BAT) thermogenesis, indicated by increases in interscapular BAT temperature (T_IBAT) of cold acclimatized (CA, kept at 4°C for 4 weeks) and room temperature acclimatized rats (RA, kept at 21°C for 4 weeks) and (2) to compare the thermoresponsiveness of VMH neurons of both groups to scrotal heating and cooling. VMH extracellular activity was recorded in male RA and CA Sprague-Dawley rats when scrotal temperatures (T_sc) were changed between 5–40°C via localized thermode (3 mm²) along with measurements of T_scs and T_IBATs. The CA-group showed significant increases in T_IBATs during scrotal cooling compared to respective T_IBATs of the RA-group. The ratio of VMH warm responsive (WRN), cold responsive (CRN) and temperature non-responsive (TNRN) neurons in the CA-group changed compared to that in the RA-group as a greater percentage of CRNs occurred in the CA-group. Also, the thermoresponsiveness of individual VMH CRNs of the CA rats was significantly increased compared to VMH CRNs of the RA-group. The results indicated that localized scrotal cooling of CA-rats (not RA-rats) can activate BAT thermogenesis. Furthermore, VMH CRNs increased their thermoresponsiveness with chronic cold exposure which may be an important neuronal adaptive response for the subsequent enhanced BAT thermogenic effector response seen in that group.     

Ventromedial hypothalamic regulation of brown adipose tissue.

The central control of brown fat thermogenesis was evaluated in seventeen rats with moveable electrodes implanted in the ventromedial hypothalamus (VMH) and adjacent structures. Brown adipose tissue and core body temperatures were monitored in response to VMH stimulation; sites which elicited a rise in brown fat temperature were observed in the dorsomedial and anterior ventromedial hypothalamus, with BAT temperature profiles varying widely in duration and peak values. Given the complexity of BAT responses to endogenous VMH signals, these varied profiles may be mediated by dissimilar VMH signals, which remain to be characterized.     

Ghrelin's effects on food motivation in rats are not limited to palatable foods

The “hunger” hormone, ghrelin, is powerfully orexigenic. Even in the absence of hunger, ghrelin delivery to rats increases consumption of chow, as well as palatable foods, and increases motivated behaviour for palatable food rewards. Inspired by the finding that ghrelin increases the selection of chow in rats offered a choice diet (lard, sucrose or chow) and even in rats bingeing on a high‐fat diet, we aimed to explore whether the effects of ghrelin on motivation extend to regular chow. Rats were conditioned to lever press for either chow or sucrose pellets in a progressive ratio (PR) operant conditioning task. The effect of acute i.c.v. delivery of ghrelin on both chow and sucrose self‐administration was determined and compared with overnight fasting (ie, when endogenous ghrelin levels are elevated). We found that ghrelin similarly increased motivated behaviour for chow and sucrose pellets. The effect of fasting on motivated behaviour for both food pellets was comparable in magnitude to that induced by ghrelin, albeit with an earlier ceiling effect during the PR session. Devaluation experiments (in which rats are offered either food reinforcer in excess prior to PR testing) did not support the hypothesis that sucrose pellets would be more difficult to devalue (as a result of their higher incentive value) than chow pellets. When exchanging the respective pellets during a PR session, chow‐conditioned rats were more motivated for sucrose pellets compared to chow pellets; however, sucrose‐conditioned rats were similarly motivated for chow pellets compared to sucrose pellets. Thus, using sucrose as a reward may increase the motivation even for less palatable foods. We conclude that the impact of ghrelin on food‐motivated behaviour in fed rats is not limited to palatable foods but extends to regular chow, and also that the magnitude of the effect is considerable compared to that of an overnight fast.     

Central Resistin Enhances Renal Sympathetic Nerve Activity via Phosphatidylinositol 3‐Kinase but Reduces the Activity to Brown Adipose Tissue via Extracellular Signal‐Regulated Kinase 1/2

Resistin is an adipokine, originally identified in adipose tissue, and its plasma levels are elevated in obesity. Characteristics of obesity include impaired metabolic regulation and cardiovascular dysfunction, such as increased sympathetic nerve activity (SNA) to the kidney and skeletal muscle vasculature. Resistin can affect energy homeostasis through central mechanisms that include reduced food intake and reduced thermogenesis, and can also increase lumbar SNA via a central action. The present study investigated: (i) the effect of centrally‐administered resistin on SNA targeting the kidney and (ii) the intracellular signalling pathways mediating the changes in SNA innervating the kidney and brown adipose tissue (BAT) induced by resistin. Intracerebroventricular resistin (7 μg) injected into overnight fasted, anaesthetised rats induced a significant increase in renal SNA by approximately 40%. This response was prevented when phosphatidylinositol 3‐kinase (PI3K) was inhibited by i.c.v. administration of LY294002 (5 μg). Resistin reduced BAT SNA and this response was delayed by 150 min when extracellular‐regulated kinase (ERK)1/2 was inhibited by i.c.v. administration of U0126. The findings indicate that resistin increases renal SNA via PI3K and reduces BAT SNA via ERK1/2.     

Intra-hypothalamic injection of thyrotropin-releasing hormone suppresses brown fat thermogenesis in the anaesthetized rat

Thyrotropin-releasing hormone (TRH) has diverse effects on body temperature in rodents, but the effector mechanisms that mediate its thermoregulatory actions are not well defined. In the present study, microinjection of 10 ng to 5 micrograms of TRH into the anterior hypothalamus (AHy) dose-dependently suppressed heat production in interscapular brown adipose tissue (BAT) in chloral hydrate-anaesthetized rats tested at a room temperature of 23 +/- 2 degrees C. This effect of TRH was mimicked by the structurally related peptides acid-TRH and luteinizing hormone releasing hormone (LH-RH), and by the TRH analog CG 3509, but not by the TRH fragments pGlu-His and His-Pro. The AHy plays a role in the regulation of BAT thermogenic activity, and the present results suggest that some of the effects of TRH on body temperature involve an AHy-mediated inhibitory action on BAT thermogenesis.