Central angiotensin 1-7 triggers brown fat thermogenesis.

We tested the hypothesis that third ventricular (3V) injections of angiotensin 1-7 (Ang 1-7) increases thermogenesis in brown adipose tissue (BAT), and whether the Mas receptor mediates this response. First, in male Siberian hamsters (n = 18), we evaluated the effect of Ang 1-7 in the interscapular BAT (IBAT) temperature and, using selective Mas receptor antagonist A-779, the role of Mas receptor in this response. Each animal received 3V injections (200 nL), with 48 h intervals: saline; Ang 1-7 (0.03, 0.3, 3, and 30 nmol); A-779 (3 nmol); and Ang 1-7 (0.3 nmol) + A-779 (3 nmol). IBAT temperature increased after 0.3 nmol Ang 1-7 compared with Ang 1-7 + A-779 at 20, 30, and 60 min. Also, 0.3 nmol Ang 1-7 increased IBAT temperature at 10 and 20 min, and decreased at 60 min compared with pretreatment. IBAT temperature decreased after A-779 at 60 min and after Ang 1-7 + A-779 at 30 and 60 min compared with the respective pretreatment. A-779 and Ang 1-7 + A-779 decreased core temperature at 60 min compared with 10 min. Then, we evaluated blood and tissue Ang 1-7 levels, and the expression of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in IBAT. Male Siberian hamsters (n = 36) were killed 10 min after one of the injections. No changes were observed in blood glucose, serum and IBAT Ang 1-7 levels, and ATGL. Ang 1-7 (0.3 nmol) increased p-HSL expression compared with A-779 and increased p-HSL/HSL ration compared with other injections. Ang 1-7 and Mas receptor immunoreactive cells were found in brain regions that coincide with the sympathetic nerves outflow to BAT. In conclusion, 3V injection of Ang 1-7 induced thermogenesis in IBAT in a Mas receptor-dependent manner.

Sympathetic and sensory innervation of brown adipose tissue.

The innervation of brown adipose tissue (BAT) by the sympathetic nervous system (SNS) is incontrovertible and, with its activation, functions as the principal, if not exclusive, stimulator of BAT thermogenesis. The parasympathetic innervation of BAT only appears in two minor BAT depots, but not in the major interscapular BAT (IBAT) depot. BAT thermogenesis is triggered by the release of norepinephrine from its sympathetic nerve terminals, stimulating ß3-adrenoceptors that turns on a cascade of intracellular events ending in activation of uncoupling protein-1 (UCP-1). BAT also has sensory innervation that may function to monitor BAT lipolysis, a response necessary for activation of UCP-1 by fatty acids, or perhaps responding in a feedback manner to BAT temperature changes. The central sympathetic outflow circuits ultimately terminating in BAT have been revealed by injecting the retrograde viral transneuronal tract tracer, pseudorabies virus, into the tissue; moreover, there is a high degree of colocalization of melanocortin 4-receptor mRNA on these neurons across the neural axis. The necessary and sufficient central BAT SNS outflow sites that are activated by various thermogenic stimuli are not precisely known. In a chronic decerebration procedure, IBAT UCP-1 gene expression can be triggered by fourth ventricular injections of melanotan II, the melanocortin 3/4 receptor agonist, suggesting that there is sufficient hindbrain neural circuitry to generate thermogenic responses with this stimulation. The recent recognition of BAT in normal adult humans suggests a potential target for stimulation of energy expenditure by BAT to help mitigate increased body fat storage.

Central melanocortin stimulation increases phosphorylated perilipin A and hormone-sensitive lipase in adipose tissues.

Norepinephrine (NE) released from the sympathetic nerves innervating white adipose tissue (WAT) is the principal initiator of lipolysis in mammals. Central WAT sympathetic outflow neurons express melanocortin 4-receptor (MC4-R) mRNA. Single central injection of melanotan II (MTII; MC3/4-R agonist) nonuniformly increases WAT NE turnover (NETO), increases interscapular brown adipose tissue (IBAT) NETO, and increases the circulating lipolytic products glycerol and free fatty acid. The WAT pads that contributed to this lipolysis were inferred from the increases in NETO. Because phosphorylation of perilipin A (p-perilipin A) and hormone-sensitive lipase are necessary for NE-triggered lipolysis, we tested whether MTII would increase these intracellular markers of lipolysis. Male Siberian hamsters received a single 3rd ventricular injection of MTII or saline. Trunk blood was collected at 0.5, 1.0, and 2.0 h postinjection from excised inguinal, retroperitoneal, and epididymal WAT (IWAT, RWAT, and EWAT, respectively) and IBAT pads. MTII increased circulating glycerol concentrations at 0.5 and 1.0 h, whereas free fatty acid concentrations were increased at 1.0 and 2.0 h. Western blot analysis showed that MTII specifically increased p-perilipin A and hormone-sensitive lipase only in fat pads that previously had MTII-induced increases in NETO. Phosphorylation increased in IWAT at all time points and IBAT at 0.5 h, but not RWAT or EWAT at any time point. These results show for the first time in rodents that p-perilipin A can serve as an in vivo, fat pad-specific indictor of lipolysis and extend our previous findings showing that central melanocortin stimulation increases WAT lipolysis.

A high fructose diet impairs spatial memory in male rats.

Over the past three decades there has been a substantial increase in the amount of fructose consumed by North Americans. Recent evidence from rodents indicates that hippocampal insulin signaling facilitates memory and excessive fructose consumption produces hippocampal insulin resistance. Based on this evidence, the present study tested the hypothesis that a high fructose diet would impair hippocampal-dependent memory. Adult male Sprague-Dawley rats (postnatal day 61) were fed either a control (0% fructose) or high fructose diet (60% of calories). Food intake and body mass were measured regularly. After 19 weeks, the rats were given 3 days of training (8 trials/day) in a spatial version of the water maze task, and retention performance was probed 48 h later. The high fructose diet did not affect acquisition of the task, but did impair performance on the retention test. Specifically, rats fed a high fructose diet displayed significantly longer latencies to reach the area where the platform had been located, made significantly fewer approaches to that area, and spent significantly less time in the target quadrant than did control diet rats. There was no difference in swim speed between the two groups. The retention deficits correlated significantly with fructose-induced elevations of plasma triglyceride concentrations. Consequently, the impaired spatial water maze retention performance seen with the high fructose diet may have been attributable, at least in part, to fructose-induced increases in plasma triglycerides.

The effects of anterior hypothalamic lesions on short-day responses in Siberian hamsters given timed melatonin infusions.

The suprachiasmatic nucleus (SCN) of the hypothalamus is an area of dense 2-[125I]Iodomelatonin binding in Siberian hamsters (Phodopus sungorus sungorus) that is suggestive of a possible role in the reception and/or relaying of melatonin (MEL) signals. Indeed, in pinealectomized male Siberian hamsters given short day (SD) MEL signals (long-duration MEL infusions), lesions of the SCN (SCNx) block testicular regression and decreases in body and fat pad masses seen in identically treated hamsters with sham lesions (SCNs). In similar studies using Syrian hamsters (Mesocricetus auratus), anterior hypothalamic lesions (AHx), but not SCNx, blocked SD MEL signal-induced gonadal regression despite the similarity in the 2-[125I]Iodomelatonin binding pattern between the two species. The discrepancy between the ability of SCNx to block the reception of SD MEL signals between the two species is puzzling, given the similarity in the reproductive status of the Syrian and Siberian hamsters to systemically administered and timed MEL infusions. One possible way of reconciling the differences between these studies was that ancillary damage to areas neighboring the SCN, including the AH, may have occurred in our attempt to achieve complete SCNx in Siberian hamsters. Therefore, the purpose of the present study was to challenge AHx Siberian hamsters with SD MEL signals. Adult male hamsters were pinealectomized, fitted with subcutaneous catheters, and given daily timed infusions of MEL for 5 or 10 h (long day-like and short day-like, respectively) or the saline vehicle for 6 wk following bilateral electrolytic, or sham (AHs) lesions of the AH. Hamsters receiving 10 h MEL infusions that lacked evidence of anatomical or functional damage to the SCN showed SD-like gonadal regression, decreases in body and fat pad mass, and food intake similar to that observed in AHs animals. In contrast, 10 h MEL-infused SCNx hamsters did not exhibit SD-like responses, a finding confirming our previous report. These data suggest that interspecies differences exist between Syrian and Siberian hamsters in central nervous system sites and pathways involved in the reception/transmission of SD MEL signals.

SCN efferents to peripheral tissues: implications for biological rhythms.

The suprachiasmatic nucleus (SCN) is the principal generator of circadian rhythms and is part of an entrainment system that synchronizes the animal with its environment. Here, we review the possible communication of timing information from the SCN to peripheral tissues involved in regulating fundamental physiological functions as revealed using a viral, transneuronal tract tracer, the pseudorabies virus (PRV). The sympathetic nervous system innervation of the pineal gland and the sympathetic outflow from brain to white adipose tissue were the first demonstrations of SCN-peripheral tissue connections. The inclusion of the SCN as part of these and other circuits was the result of lengthened postviral injection times compared with those used previously. Subsequently, the SCN has been found to be part of the sympathetic outflow from the brain to brown adipose tissue, thyroid gland, kidney, bladder, spleen, adrenal medulla, and perhaps the adrenal cortex. The SCN also is involved in the parasympathetic nervous system innervation of the thyroid, liver, pancreas, and submandibular gland. Individual SCN neurons appear connected to more than one autonomic circuit involving both sympathetic and parasympathetic innervation of a single tissue, or sympathetic innervation of two different peripheral tissues. Collectively, the results of these PRV studies require an expansion of the traditional roles of the SCN to include the autonomic innervation of peripheral tissues and perhaps the modulation of neuroendocrine systems traditionally thought to be controlled solely by hypothalamic stimulating/inhibiting factors.

Effect of melatonin infusion duration and frequency on gonad, lipid, and body mass in pinealectomized male Siberian hamsters.

The goal of this study was to discriminate between two hypotheses regarding how the circadian rhythm of pineal melatonin (MEL) production transmits photoperiodic information: (1) A circadian rhythm of sensitivity to MEL regulates the hormone's effect; (2) the duration of the MEL signal, rather than its circadian timing, is the critical parameter of the MEL rhythm. The experiment examined the response of pinealectomized (PINX) male Siberian hamsters to 10-hr (short-day-type) versus 6-hr (long-day-type) duration MEL infusions (10 ng/infusion) in cycles with period lengths (T) of 18, 24, 36, and 48 hr. After cannula implantation, animals were moved from LD 16:8 to LD 10:14 (lights-on from 0500 to 1500 hr, EST), where the timed infusions began. Additional T 24 cycles included as controls employed 18-hr MEL, 18-hr saline (SAL), and 10-hr SAL infusions: Body weight and food intake were measured weekly. After 6 weeks, animals were killed; blood samples were taken for radioimmunoassay (RIA) of serum follicle-stimulating hormone (FSH) and prolactin (PRL); and terminal body, epididymal white adipose tissue (EPIWAT), and paired testis weights were recorded. Six-hour MEL infusions failed to induce short-day-type effects, regardless of the period (T) of the infusion cycle. In contrast, compared to SAL and 6-hr MEL infusions, 10-hr MEL resulted in decreases in body, EPIWAT, and testis weights in T 24, but not in T 36 or T 48. In T 18, testis, body, and EPIWAT mass were decreased, but not to the same extent as in T 24. Similarly, daily 18-hr MEL infusions (T24) were less effective as a short-day stimulus than were 10-hr MEL infusions. The effectiveness of 10-hr, but not 6-hr, MEL infusions in T 18 and T 24 is consistent with the duration hypothesis and argues against the circadian hypothesis. Neither hypothesis could have predicted that all infusion cycles of T greater than or equal to 36 hr, regardless of the infusion durations, would fail to elicit short-day-type responses. This outcome suggests a need for relatively frequent (T less than 36 hr) MEL stimulation in addition to the requirement for adequate duration of each MEL infusion.

Neural control of white, beige and brown adipocytes.

Reports of brown-like adipocytes in traditionally white adipose tissue (WAT) depots occurred ~30 years ago, but interest in white adipocyte 'browning' only has gained attention more recently. We integrate some of what is known about the sympathetic nervous system (SNS) innervation of WAT and brown adipose tissue (BAT) with the few studies focusing on the sympathetic innervation of the so-called 'brite' or 'beige' adipocytes that appear when WAT sympathetic drive increases (for example, cold exposure and food deprivation). Only one brain site, the dorsomedial hypothalamic nucleus (DMH), selectively browns some (inguinal WAT (IWAT) and dorsomedial subcutaneous WAT), but not all WAT depots and only when DMH neuropeptide Y gene expression is knocked down, a browning effect is mediated by WAT SNS innervation. Other studies show that WAT sympathetic fiber density is correlated with the number of brown-like adipocytes (multilocular lipid droplets, uncoupling protein-1 immunoreactivity) at both warm and cold ambient temperatures. WAT and BAT have sensory innervation, the latter important for acute BAT cold-induced temperature increases, therefore suggesting the possible importance of sensory neural feedback from brite/beige cells for heat production. Only one report shows browned WAT capable of producing heat in vivo. Collectively, increases in WAT sympathetic drive and the phenotype of these stimulated adipocytes seems critical for the production of new and/or transdifferentiation of white to brite/beige adipocytes. Selective harnessing of WAT SNS drive to produce browning or selective browning independent of the SNS to counter increases in adiposity by increasing expenditure appears to be extremely challenging.

Photoperiodic control of seasonal body weight cycles in hamsters.

Syrian (Mesocricetus auratus) and Siberian (Phodopus sungorus sungorus) hamsters exhibit seasonal changes in body weight mainly by altering their carcass lipid stores. These seasonal changes are triggered largely by the photoperiod. Although both species exhibit gonadal regression when exposed to short photoperiods ("winterlike") daylength), they show opposite body weight changes. Syrian hamsters gain weight, but Siberian hamsters lose weight following short photoperiod exposure. Syrian hamsters prepare for overwintering by increasing energy stored as carcass lipid. In contrast, Siberian hamsters decrease their metabolic mass and therefore require lower energy intake for energy maintenance. In Syrian, and perhaps Siberian hamsters the short day-induced weight changes are exaggerated by high fat diets. Both species show photoperiod-induced changes in body weight without changing their food intake, suggesting a metabolic basis for these effects. In Syrian hamsters, the obesity is not secondary to gonadal regression, whereas in Siberian hamsters, the decrease in body weight is independent of the gonads for males but may be dependent upon the gonads in females. The pineal gland and its hormone, melatonin, are important transducers of photoperiodic signals in hamsters. This is certainly true for Siberian hamsters, in which pinealectomy blocks the short day-induced body weight loss. In contrast, pinealectomy has little effect on short day-induced weight gain in Syrian hamsters. Nevertheless, in both species, the body weight and gonadal changes induced by short day exposure are mimicked by systemic administration of melatonin in long day-housed animals. Thus, for these two hamster species, the same hormone, melatonin, produces opposite effects on body weight but does so by affecting the same carcass component. The target sites of action for the effects of melatonin on body weight change, energy metabolism, and reproductive status are not known. However, the suprachiasmatic and paraventricular nuclei of the hypothalamus are potentially important sites of action. The target site(s) and mechanism(s) of action for the pineal/melatonin-independent effect of photoperiod on body weight in Syrian hamsters are also unknown. This photoperiodic response is highly unusual among mammals in that it is not pineal-dependent. Studies of the mechanisms underlying these body weight changes in Syrian and Siberian hamsters may provide fundamental knowledge about how environmental influences affect obesity and they may also provide insight into the various strategies for overwintering shaped by natural selection.(ABSTRACT TRUNCATED AT 400 WORDS)

The regulation of total body fat: lessons learned from lipectomy studies.

Surgical removal of body fat (partial lipectomy) is a means of directly reducing fat such that metabolic and behavioral responses can be readily attributed to the lipid deficit. If total body fat is regulated, then lipectomy should trigger compensatory increases in nonexcised white adipose tissue (WAT) mass and/or regrowth at excision sites. Many species, including laboratory rats and mice, show lipectomy-induced compensatory recovery of body fat. Those animals exhibiting naturally occurring annual adiposity cycles, such as ground squirrels and hamsters, do so most impressively reaching seasonally appropriate body fat levels indistinguishable from controls. Reparation of the lipid deficit occurs without an increase in food intake, and generally through enlargement of non-excised WAT mass, rather than regrowth of excised WAT. A body fat regulatory system involving humoral and sensory neural inputs to the brain as well as sympathetic neural outputs from brain to adipose tissue is presented. Collectively, the lipectomy model appears useful for testing mechanisms controlling adiposity, or individual depot growth, and offers insight into how lipid stores fluctuate naturally.

Photoperiodic control of body weight and energy metabolism in Syrian hamsters (Mesocricetus auratus): role of pineal gland, melatonin, gonads, and diet.

The effects of photoperiod and the pineal hormone melatonin on the regulation of body weight and energy metabolism were examined in Syrian hamsters, Mesocricetus auratus. Short photoperiod-housed female and male hamsters showed increases in body weight gain, feed efficiency, carcass lipid, brown adipose tissue mass, and thermogenic capacity. These effects of short photoperiods were mimicked by afternoon melatonin injections to hamsters in long-day photoperiods and were exaggerated in hamsters fed high fat diets. To determine the role of the gonads in these effects, ovariectomized hamsters were treated similarly and found to exhibit changes in body weight and energy metabolism that were 80-90% of those in gonadally intact hamsters. The role of the pineal gland in short photoperiod-induced body weight gain was examined in sham-pinealectomized and pinealectomized hamsters. Short photoperiod-induced increases in body weight were seen in both pinealectomized and sham-pinealectomized hamsters. Thus, pinealectomy blocks the effects of short photoperiods on reproductive function and thyroid activity, but not on body weight regulation. These results suggest that the effects of short photoperiods on body weight and energy metabolism are mediated by multiple, redundant mechanisms involving decreases in gonadal hormone secretion, changes in melatonin secretion, and gonad- and pineal-independent changes. All of the effects of short photoperiods are exaggerated in hamsters fed a high fat diet. These changes may represent adaptive preparatory responses that enhance winter survival in Syrian hamsters.

Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat.

Central administration of melanocortin 3 and 4 receptor (MC3/4-R) agonists increases energy expenditure, with the hypothalamus commonly held as the primary site of action. It is also clear, however, that MC4-R are expressed in caudal brainstem structures of relevance to the control of energy expenditure. Three experiments investigated whether hindbrain MC-R contribute to the energy expenditure effects of central MC3/4-R agonist treatments; in each, we examined the effect of fourth intracerebroventricular (i.c.v.) administration of a MC3/4-R agonist, MTII (three injections, each separated by 12 h), on uncoupling protein 1 (UCP-1) gene expression in brown adipose tissue (BAT). First, we compared the effects of fourth and third i.c.v. administration of MTII and found that the hindbrain and forebrain treatments were equally effective at elevating UCP-1 mRNA expression in BAT compared with the respective vehicle-treated group results. A second experiment demonstrated that the fourth i.c.v. MTII-induced rise in UCP-1 expression was mediated by sympathetic outflow to BAT by showing that this response was abolished by surgical denervation of BAT. In the third experiment, we showed that chronic decerebrate rats, like their neurologically intact controls, elevated UCP-1 mRNA expression in response to fourth i.c.v. MTII administration. Taken together, the results indicate that: 1) there is an independent caudal brainstem MC3/4-R trigger for a sympathetically stimulated elevation in BAT UCP-1 gene expression, and 2) the MTII-induced rise in UCP-1 expression can be mediated by circuitry intrinsic to the caudal brainstem and spinal cord.

The biology of white adipocyte proliferation.

Expanded adipose tissue mass increases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease, and some forms of cancer. Therefore, it is imperative that we understand the mechanisms by which fat pads expand. The enlargement of fat cells during the development of obesity has been previously hypothesized to be a triggering factor for the proliferation of new fat cells. There is now a preponderance of evidence that adipose tissue is a source of growth factors such as IGF-I, IGF binding proteins, TNF alpha, angiotensin II, and MCSF that are capable of stimulating proliferation. The relative importance of these autocrine/paracrine factors in the normal control of preadipocyte proliferation is unknown. In addition, the proliferative response of preadipocytes to the paracrine milieu is undoubtedly modulated by neural inputs to fat tissue and/or serum factors. Together, these multiple regulatory controls orchestrate overall and region-specific adipose tissue cellularity responses associated with the development of hyperplastic obesity. Both in vivo and in vitro studies are needed to understand the complex, interacting physiological mechanisms by which growth of this important organ is regulated.

Co-expression of melatonin (MEL1a) receptor and arginine vasopressin mRNAs in the Siberian hamster suprachiasmatic nucleus.

Durational melatonin signals, cued by the photoperiod and generated by the pineal gland, are processed in the brain to induce seasonally appropriate physiological and behavioural adaptations. The melatonin receptor subtype MEL1a (also known as mt1) appears to regulate seasonal responses. Single label in situ hybridization for MEL1a receptor mRNA revealed labelled cells in several brain regions of Siberian hamsters, including the suprachiasmatic nucleus, the paraventricular nucleus of the thalamus, and the reuniens nucleus of the thalamus. To characterize suprachiasmatic nucleus cells containing MEL1a receptor mRNA, we used 35S-labelled cRNA probes for MEL1a receptor mRNA in combination with digoxigenin-labelled cRNA probes for vasopressin, somatostatin, or orphan retinoid Z receptor beta (RZRbeta; a putative nuclear melatonin receptor). Cells in the suprachiasmatic nucleus that contained MEL1a receptor mRNA also contained mRNAs for vasopressin and RZRbeta, but not for somatostatin. These data suggest that suprachiasmatic nucleus vasopressin cells may respond to melatonin signals, raising the possibility that suprachiasmatic nucleus vasopressin output mediates some of the effects of melatonin on seasonal or circadian responses.

Sympathoadrenal system differentially affects photoperiodic changes in humoral immunity of Siberian hamsters (Phodopus sungorus).

Siberian hamsters (Phodopus sungorus) rely on photoperiod as a primary cue to coordinate seasonally appropriate changes in physiology and behaviour. Among these seasonal changes is reduced immune function in short 'winter-like' days, compared to long 'summer-like' days. Previous evidence suggests that immune function is regulated, in part, by the sympathoadrenal system. The precise role of the sympathoadrenal system in regulating photoperiodic changes in immune function, however, remains unspecified. The goal of the present study was to examine the differential contributions of direct sympathetic innervation of immune target tissue, as well as adrenal medullary catecholamines, to photoperiodic changes in immune function in male Siberian hamsters. In Experiment 1, hamsters underwent either bilateral surgical removal of the adrenal medulla (ADMEDx), or sham surgeries, and were maintained in long (LD 16 : 8) or short days (LD 8 : 16). In Experiment 2, hamsters received either surgical denervation of the spleen, or sham surgeries, and were then housed in long or short days. Serum anti-KLH IgG concentrations and splenic norepinephrine (NE) content were determined in both experiments. Short-day hamsters had reduced humoral immunity compared to long-day hamsters. ADMEDx reduced immune function, but only in long-day hamsters. In contrast, splenic denervation reduced humoral immunity, but only in short-day hamsters. Splenic NE content was increased in short days and by ADMEDx. NE content was markedly reduced in denervated hamsters compared to sham-operated hamsters. Collectively, these results suggest that the sympathoadrenal system is associated with photoperiodic changes in immune function.

Dietary self-selection in intact, ovariectomized, and estradiol-treated female rats.

The effects of estrogenic stimulation on diet selection were examined in intact, estrous cycling rats, ovariectomized (OVX) rats, and OVX rats given estradiol benzoate (EB) hormone replacement therapy. In Experiment 1, OVX was associated with the nearly exclusive choice of the more calorically dense diet of a pair of diets varying in the concentration of one of the three basic macronutrients (i.e., fat, carbohydrate, and protein), an effect that was decreased by EB administration. In the second experiment, dietary self-selection was examined in intact, estrous cycling rats given access to an isocaloric diet triplet of fat, carbohydrate (CHO), and protein. Total caloric intake and body weight did not vary across the estrous cycle. However, diet selection did vary. Fat intake increased; CHO and, to a lesser extent, protein intake decreased during estrus. An opposite diet selection occurred during diestrus. In Experiment 3, OVX resulted in progressive increases in CHO and protein intake, with a concurrent decrease in fat consumption. The EB treatment partially reversed this diet selection profile (Experiment 4). These results were confirmed by diet pairs with both naturally occurring and experimentally produced estrogenic stimulation (Experiments 5 and 6). These data are consistent with the findings of previous research demonstrating estrogenic reduction in CHO intake with standard high-CHO commercial diets. In addition, an increase in fat intake during estrogenic stimulation was found.

Effects of interscapular brown adipose tissue denervation on body weight and energy metabolism in ovariectomized and estradiol-treated rats.

Ovariectomy-induced increases and estradiol-induced decreased in body weight cannot be fully accounted for by changes in energy intake and appear to reflect alterations in thermogenesis. Because changes in energy expenditure have been linked to altered sympathetic nervous system (SNS) activity in brown adipose tissue (BAT), the role of estradiol in thermogenesis and body weight, as mediated by the SNS innervation of interscapular BAT (IBAT), was examined. The IBAT of ovariectomized rats was bilaterally or unilaterally surgically denervated. The chow-fed, bilaterally denervated group gained more weight than the unilaterally denervated or sham-operated group, an effect that was exaggerated by sucrose feeding. Food intake did not differ among the groups within each dietary condition. Estradiol benzoate (EB) injections decreased body weight in all groups. Bilateral, and to a lesser extent, unilateral IBAT denervation blocked the EB-induced increase in thermogenesis. Treatment with EB increased IBAT wet weight regardless of surgical treatment. Because IBAT denervation markedly decreased lipoprotein lipase activity and fatty acid synthesis/uptake, the estradiol-induced increase in denervated IBAT wet weight is most likely due to decreased lipolysis produced by the surgical sympathectomy. These results are discussed in terms of the role of the SNS and IBAT in the mediation of estradiol-induced changes in body weight and energy metabolism.

Photoperiod-peptide interactions in the energy intake of Siberian hamsters.

Siberian hamsters (Phodopus sungorous sungorous) decrease their food intake when exposed to short ("winter-like") photoperiods. The cause of this naturally-occurring hypophagia is unknown, but it may be due to a heightened sensitivity to the factors that normally terminate food intake in long photoperiods, such as the putative satiety peptides. The purpose of the present investigation was to test whether there would be an enhanced sensitivity to the inhibitory effects of some of these peptides on food intake in short relative to long days. Ad lib-fed, adult female Siberian hamsters were housed in a long photoperiod (LD 14:10) and injected with bombesin, glucagon, cholecystokinin octapeptide (CCK-8) and calcitonin (CT). Food intake was monitored 1, 2, 4, 6, and 24 hr post-injection. Bombesin and glucagon had no effect on food intake in long day-housed hamsters. CCK-8 and CT inhibited food intake; however, CCK-8 did so without any apparent behavioral disruption, while CT produced a marked and prolonged depression of behavior. After 10 weeks of exposure to a short photoperiod (LD 8:16) the hamsters were tested again. The previously ineffective dose of bombesin greatly inhibited food intake following short photoperiod exposure. In addition, an increased inhibition of food intake by CCK-8 was also found. In contrast, glucagon did not decrease food intake and CT still produced its non-specific, behaviorally disruptive effects. To our knowledge, this is the first demonstration that the effectiveness of a putative satiety peptide can be dependent upon a change in the photoperiod.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel method for localized, functional sympathetic nervous system denervation of peripheral tissue using guanethidine.

A simple technique for local chemical sympathectomy of peripheral tissues is described using guanethidine. Multiple microinjections of guanethidine were made into inguinal or epididymal white adipose tissue (IWAT and EWAT) pads or spleens of hamsters. Guanethidine virtually abolished the sympathetic innervation of both EWAT and IWAT, as measured by the absence of significant norepinephrine (NE) tissue content two weeks later and as suggested by the two-fold increase in IWAT mass characteristic of surgically induced WAT denervation. These measures were not affected in the contralateral pads given equivolumetric injections of saline. Guanethidine injections into the spleen lead to a functional sympathectomy, as indicated by significant depletions of NE content. Because guanethidine treatment did not decrease body mass, induce ptosis, or spread to closely associated adjacent tissue (contralateral EWAT pad), no chemical-induced malaise or global sympathetic denervation was suggested. Guanethidine was more effective than two other local sympathectomy treatments, injections of the sympathetic neurotoxin anti-dopamine-beta-hydroxylase saporin or surgical denervation, in decreasing IWAT NE content and increasing IWAT pad mass. Collectively, these results suggest that locally applied, chemical sympathectomy with guanethidine provides an effective, restricted method for sympathectomizing WAT, spleen and likely other peripheral tissues.

Disproportionate increases in locomotor activity in response to hormonal and photic stimuli following regional neurochemical depletions of serotonin.

The role of forebrain serotonin in behavior-related energy output was assessed in two locomotor activity tests conducted 3 and 6 months after bilateral, intrahypothalamic microinfusion of the serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). The serotonin-depleted animals exhibited a long-lasting and stable increase in energy expenditure as locomotor activity. This increased activity was investigated at the behavioral level by relating the hyperactivity to estrous cycle, photoperiod and body weight. Although the serotonin depletion-induced hyperactivity occurred in all photoperiod and estrous cycle stages, its magnitude was disproportionately increased during light and estrus. This hyperactivity could not be related to decreases in body weight because the serotonin-depleted animals weighed significantly more than the control animals. These animals responded to the weight loss that normally accompanies wheel running by increasing their activity to the same proportion as the other groups. The neuroanatomical and neurochemical substrate of the increased locomotor activity was investigated with a regional neurochemical assay for serotonin, dopamine and norepinephrine. This assay revealed that the toxin had no effect on dopamine or norepinephrine in any structure analyzed; however, serotonin was depleted in the hippocampus, septum and, to a lesser degree, in the hypothalamus. Serotonin levels were negatively correlated with overall activity. The magnitude of the disproportionate increase in activity during light and estrus was negatively correlated with hippocampal serotonin level. These results indicate that forebrain depletions of serotonin differentially affect the control of activity exerted by the phases of the photoperiod and estrous cycle. However, the modulation of activity levels by decreases in body weight remains intact.