The role of oestrogen in determining sexual dimorphism in energy balance.

Energy balance is determined by caloric intake and the rate at which energy is expended, with the latter comprising resting energy expenditure, physical activity and adaptive thermogenesis. The regulation of both energy intake and expenditure exhibits clear sexual dimorphism, with young women being relatively protected against weight gain and the development of cardiometabolic diseases. Preclinical studies have indicated that females are more sensitive to the satiety effects of leptin and insulin compared to males. Furthermore, females have greater thermogenic activity than males, whereas resting energy expenditure is generally higher in males than females. In addition to this, in post-menopausal women, the decline in sex steroid concentration, particularly in oestrogen, is associated with a shift in the distribution of adipose tissue and overall increased propensity to gain weight. Oestrogens are known to regulate energy balance and weight homeostasis via effects on both food intake and energy expenditure. Indeed, 17ß-oestradiol treatment increases melanocortin signalling in the hypothalamus to cause satiety. Furthermore, oestrogenic action at the ventromedial hypothalamus has been linked with increased energy expenditure in female mice. We propose that oestrogen action on energy balance is multi-faceted and is fundamental to determining sexual dimorphism in weight control. Furthermore, evidence suggests that the decline in oestrogen levels leads to increased risk of weight gain and development of cardiometabolic disease in women across the menopausal transition.

Brown adipose tissue thermogenesis in polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with increased obesity with a greater propensity to weight gain and a lack of sustainable lifestyle interventions. Altered brown adipose tissue (BAT) thermogenesis is a potential contributor to obesity in PCOS. BAT activity and modulation have not been studied in PCOS. This observational study explored BAT thermogenesis and its associations in women with and without PCOS. PARTICIPANTS AND METHODS: Cutaneous temperature was recorded from supraclavicular (indicator of BAT activity) and upper arm regions using dataloggers (SubCue, Calgary, Canada) in a cross-sectional substudy, nested within a randomized control trial, of community-recruited premenopausal women with (n = 47, Rotterdam diagnostic criteria) and without (n = 11) PCOS. RESULTS: Complete temperature data were available in 44 PCOS (mean age: 30.0 ± 6.2, mean BMI: 29.3 ± 5.5) and 11 non-PCOS (mean age: 33.0 ± 7.0, mean BMI: 25 ± 3) women. Women with PCOS had lower supraclavicular skin temperature compared to controls overall (33.9 ± 0.7 vs 34.5 ± 1, P < 0.05) and during sleep (34.5 ± 0.6 vs 35.2 ± 0.9, P < 0.001). In the PCOS group, supraclavicular skin temperature overall and over sleep and waking hours correlated inversely with testosterone (r = -0.41 P < 0.05, r = -0.485 P < 0.01 and r = -0.450 P < 0.01 respectively). Testosterone levels explained approximately 15%, 30% and 20% of the variability in supraclavicular skin temperature overall and over sleep and waking hours in women with PCOS, respectively. CONCLUSION: Women with PCOS have lower BAT activity compared to controls. BAT thermogenesis is negatively associated with androgen levels in PCOS.

Exercise counteracts the homeostatic decrease in thermogenesis caused by caloric restriction in sheep.

Caloric restriction causes a homeostatic reduction in thermogenesis. We aimed to determine whether exercise could counteract this. We studied four groups of normal-weight ewes ( n = 5), including control sedentary fed ad libitum, exercise fed ad libitum (30 min/d, 5 d/wk), diet-restricted (70% of ad libitum food intake), and combined diet and exercise. Temperature probes implanted in sternal and retroperitoneal adipose tissue and skeletal muscle measured thermogenesis. After the 4-wk intervention, hypothalami were collected for in situ hybridization, and fat and muscle biopsies were collected for real-time PCR and Western blotting. Combined diet and exercise reduced adiposity ( P < 0.05). Caloric restriction alone reduced overnight temperatures in sternal and retroperitoneal fat ( P < 0.05), which was counteracted by exercise ( P < 0.05). Exercise did not induce expression of cellular markers of browning in adipose tissue. There was no effect of diet or exercise on skeletal muscle thermogenesis. Combined diet and exercise increased the expression of neuropeptide Y and agouti-related protein in the hypothalamic arcuate nucleus ( P < 0.05), consistent with reduced adiposity. Gene expressions of key hypothalamic appetite-regulating peptides were not associated with altered thermogenesis. We demonstrate that exercise counteracts the inhibitory effect of caloric restriction to restore thermogenesis in adipose tissue of sheep.-Fuller-Jackson, J.-P., Clarke, I. J., Rao, A., Henry, B. A. Exercise counteracts the homeostatic decrease in thermogenesis caused by caloric restriction in sheep.

Lipopolysaccharide reduces gonadotrophin-releasing hormone (GnRH) gene expression: role of RFamide-related peptide-3 and kisspeptin.

RFamide-related peptide (RFRP)-3 reduces luteinising hormone (LH) secretion in rodents. Stress has been shown to upregulate the expression of the RFRP gene (Rfrp) with a concomitant reduction in LH secretion, but an effect on expression of the gonadotrophin-releasing hormone (GnRH) gene (Gnrh1) has not been shown. We hypothesised that lipopolysaccharide (LPS)-induced stress affects expression of Rfrp, the gene for kisspeptin (Kiss1) and/or Gnrh1, leading to suppression of LH levels in rats. Intracerebroventricular injections of RFRP-3 (0.1, 1, 5 nmol) or i.v. LPS (15µgkg-1) reduced LH levels. Doses of 1 and 5 nmol RFRP-3 were then administered to analyse gene expression by in situ hybridisation. RFRP-3 (5 nmol) had no effect on Gnrh1 or Kiss1 expression. LPS stress reduced GnRH and Kiss1 expression, without affecting Rfrp1 expression. These data indicate that LPS stress directly or indirectly reduces Gnrh1 expression, but this is unlikely to be due to a change in Rfrp1 expression.

Innate Obesity, Revealed by Selection Markers, Confers Significant Imprint of Hypothalamic Genes Controlling Energy Expenditure.

The incidence of obesity is rapidly escalating and has reached epidemic proportions. In all species, including rodents, humans, and sheep, there is large variation in the degree of weight gain across individuals in response to an obesogenic environment. This individual variation is, at least in part, determined by innate differences in energy expenditure, of which adaptive thermogenesis is a key component. The hypothalamus is essential to the control of body weight and adiposity. Appetite-regulating peptides within the hypothalamus exert reciprocal effects on food intake and energy expenditure, such that neuropeptides that stimulate food intake inhibit thermogenesis and vice versa. This review discusses the role of the hypothalamic neuropeptides in determining innate predisposition to obesity in 3 animal models being obesity-prone and obesity-resistant rodents, genetically lean and obese sheep, and animals selected for high/low cortisol responsiveness. In rodents, leptin resistance is a primary feature of the propensity to become obese. This contrasts that of larger mammals, such as sheep, where altered susceptibility to obesity manifests within the melanocortin and/or orexin pathways. This review highlights fundamental species differences within the hypothalamus that lead to altered susceptibility to weight gain and increased propensity to become obese.

High cortisol responses identify propensity for obesity that is linked to thermogenesis in skeletal muscle.

Subjects characterized as cortisol high responders (HRs) consume more calories after stress, but it is unknown whether cortisol responsiveness predicts a propensity for obesity. Female sheep with either high or low cortisol responses to adrenocorticotropin (ACTH) were identified. Body composition was similar in HRs and cortisol low responders (LRs), but the HRs had greater (P<0.01) adiposity than did the LRs (40.5±0.7 vs. 35.8±1.4%) after high-energy feeding, despite comparable food intake. Postprandial thermogenesis in muscle temperature was 0.8 ± 0.08°C higher in the LRs than in the HRs (P<0.01), whereas feeding-induced changes in fat temperature were similar. Leptin and insulin sensitivity were similar in the HRs and LRs. Feeding lowered (P<0.001) the respiratory control ratio in muscle (HRs 9.2±0.8-5.2±1.2; LRs 8.4±0.5-5.2±0.7), indicative of increased uncoupled respiration. Also in muscle, the feeding-induced increases in uncoupling protein (UCP)-3 (fold increase: HRs, 2.4; LRs, 2.0), ryanodine 1 receptor (RyR1; fold increase: HRs 3.1; LRs 2.1), and sarcoendoplasmic reticulum Ca(2+)-dependent ATPase (fold increase: HRs 1.5; LRs 1.6) were equivalent in the HRs and LRs. Sequencing of mitochondrial DNA revealed no haplotypic differences between the 2 groups. We conclude that predisposition to obesity can be predicted by cortisol responsiveness to an ACTH challenge and that the response is due to innate differences in muscle thermogenesis.

Cochlear implant users' spectral ripple resolution.

This study revisits the issue of the spectral ripple resolution abilities of cochlear implant (CI) users. The spectral ripple resolution of recently implanted CI recipients (implanted during the last 10 years) were compared to those of CI recipients implanted 15 to 20 years ago, as well as those of normal-hearing and hearing-impaired listeners from previously published data from Henry, Turner, and Behrens [J. Acoust. Soc. Am. 118, 1111-1121 (2005)]. More recently, implanted CI recipients showed significantly better spectral ripple resolution. There is no significant difference in spectral ripple resolution for these recently implanted subjects compared to hearing-impaired (acoustic) listeners. The more recently implanted CI users had significantly better pre-operative speech perception than previously reported CI users. These better pre-operative speech perception scores in CI users from the current study may be related to better performance on the spectral ripple discrimination task; however, other possible factors such as improvements in internal and external devices cannot be excluded.

Postprandial heat production in skeletal muscle is associated with altered mitochondrial function and altered futile calcium cycling.

This study aimed to determine whether postprandial temperature excursions in skeletal muscle are consistent with thermogenesis or altered blood flow. Temperature probes were implanted into the vastus lateralis muscle of ovariectomized ewes, and blood flow was assessed using laser-Doppler flowmetry (tissue flow) and transit-time ultrasound flowmetry (femoral artery flow). The animals were program-fed between 1100 and 1600, and temperature and blood flow were measured during intravenous administration of either isoprenaline or phenylephrine and during feeding and meal anticipation. In addition, muscle biopsies were collected prefeeding and postfeeding to measure uncoupling protein (UCP) expression and mitochondrial function, as well as indices of calcium cycling (ryanodine 1 receptor: RyR1 and sarcoendoplasmic calcium-dependent ATPases SERCA1/ SERCA2a). Isoprenaline increased femoral artery blood flow, whereas phenylephrine reduced blood flow. At high doses only, isoprenaline treatment increased heat production in muscle. Phenylephrine treatment did not alter muscle temperature. Meal anticipation was evoked in fasted animals (previously program-fed) that were housed beside animals that were fed. Increases in muscle temperature were elicited by feeding and meal anticipation, without changes in blood flow during either paradigm. Analyses of respiration in isolated mitochondria indicated that the postprandial increase in heat production was associated with an increase in state 4 respiration, without increased UCP1, UCP2, or UCP3 expression. Feeding increased the expression of RyR1 and SERCA2a. We conclude that excursions in muscle temperature may occur independent of blood flow, suggesting that postprandial heat production is driven by altered mitochondrial function and changes in calcium cycling.

Gonadotropin-inhibitory hormone is a hypothalamic peptide that provides a molecular switch between reproduction and feeding.

OBJECTIVE: Gonadotropin-inhibitory hormone (GnIH)-3 is a neuropeptide that plays a major role in the regulation of reproduction and feeding in mammals. MATERIALS AND METHODS: We measured endocrine and behavioural parameters of reproduction in sheep, and sexual behaviour in sheep, mice and cynomolgus monkeys. In addition, GnIH gene expression (in situ hybridization) was examined in ewes, and effects of GnIH-3 on food intake and energy expenditure were measured in various species. GnIH-3 was infused (i.v.) into ewes after an i.m. injection of estradiol benzoate to determine whether the peptide blocks the surge in luteinizing hormone (LH) secretion. RESULTS: GnIH gene expression was reduced in the preovulatory period in ewes. Infusion (i.v.) of GnIH-3 blocked the estrogen-induced LH surge (in ewes). Intracerebroventricular infusion had no effect on female or male sexual behaviour in each of the three species, but increased food intake. There were no effects on energy expenditure in sheep or rats. GnIH increased fos protein (immunohistochemistry) was seen in orexigenic neurons (in sheep and rats), but also in anorexigenic neurons (in sheep). CONCLUSIONS: GnIH-3 reduces reproductive hormone levels and increases food intake in mammals without reducing energy expenditure. There is minimal effect on reproductive behaviour. The dual effect on reproduction and feeding suggests that GnIH-3 provides a molecular switch between these two functions. Blockade of the positive feedback effect of estrogen with parenteral infusion indicates that this peptide may have utility as a blocker of reproductive function in mammals.

The role of sleep in PCOS: what we know and what to consider in the future.

INTRODUCTION: Sleep disturbance and clinical sleep conditions disrupt endocrine signals, energy expenditure and nutritional intake. Women with polycystic ovary syndrome (PCOS) are at higher risk of sleep disturbances and clinical conditions. It is possible that sleep may contribute to the exacerbation of PCOS. This review aims to explore the relationship between sleep and chronic disease, particularly in women with PCOS. AREAS COVERED: This review narratively explores what sleep is, how to measure sleep and the possible mechanisms that support the link between sleep in adipose tissue deposition, insulin resistance and the presentation of PCOS. EXPERT OPINION: Research shows that disturbed sleep and clinical sleep conditions disrupt energy expenditure. This may increase adipose tissue deposition and exacerbate insulin resistance which are known to worsen the presentation of PCOS. Further, sleep disturbance in women with PCOS may ameliorate any positive lifestyle changes made after diagnosis. Cognitive behavioural therapy interventions for sleep are a successful strategy for the management of sleep disturbances in the general population. However, such interventions are yet to be trialled in women with PCOS. Given the proposed implications, interventions to improve sleep could provide additional support for women with PCOS to successfully implement lifestyle strategies and should be further investigated.

Central infusion of leptin does not increase AMPK signaling in skeletal muscle of sheep.

In sheep, central leptin infusion reduces food intake and increases energy expenditure in adipose tissue and skeletal muscle. The mechanisms for these peripheral effects of central leptin in sheep are not known but, on the basis of rodent studies, may involve AMPK. In mice, central leptin acutely increases both skeletal muscle AMPK activation and glucose uptake. Thus, to investigate whether these effects exist in higher-order mammals, ovariectomized Corriedale ewes (n = 4 per group) received a continuous lateral ventricular infusion (60 µl/h) of either leptin (50 µg/h) or artificial cerebrospinal fluid (aCSF; CON) for 8 days. Tritiated glucose (3-(3)H-glucose) was infused intravenously for calculation of whole body glucose turnover during both acute (6 h) and chronic (7-8 days) leptin/aCSF infusion. Muscle biopsies were also obtained. Leptin infusion reduced (P < 0.05) food intake and body weight, and it also increased plasma epinephrine concentration at 6 h and 7 days, suggesting increased sympathetic nerve activity. Despite this, and in contrast to rodent studies, central leptin infusion did not increase skeletal muscle AMPKα Thr(172) phosphorylation or ACCß Ser(221) phosphorylation. Surprisingly, the glucose rate of appearance (glucose Ra) and rate of disappearance (glucose Rd) were reduced by both acute and chronic leptin infusion. Direct infusion of the AMPK activator 5-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) into the femoral artery increased skeletal muscle AMPK phosphorylation. In conclusion, although central leptin infusion in sheep caused the predicted reduction in food intake and increases plasma epinephrine concentration, it had no effect on AMPK activation in skeletal muscle and actually reduced glucose disposal. This suggests that there are species differences in the peripheral responses to central leptin infusion.

Glucagon-like peptide-1 control of GnRH secretion in female sheep.

The role of glucagon-like peptide-1 (GLP-1) on gonadotropin-releasing hormone (GnRH) secretion was investigated in ovariectomised (OVX) ewes, in which GnRH and luteinising hormone (LH) secretion had been restrained by treatment with oestrogen and progesterone. Guide tubes for microinjection were placed above the median eminence (ME) and the animals were allowed to recover for 1 month. Jugular venous blood samples were taken via cannulae at 10 min intervals. Vehicle (50 nL) was injected into the ME at 2 h, followed by injection of GLP-1 ((7-36)-amide - 0.5 or 1 nmol) or its receptor agonist, exendin-4 (0.5 nmol) at 4 h (n = 5). Plasma LH levels were quantified as a surrogate measure of GnRH secretion. GLP-1 microinjection into the ME elicited a large amplitude LH pulse in jugular plasma, the effect was greater at the higher dose. Exendin-4 microinjection caused a large, sustained increase in plasma LH levels. To determine how GLP-1 might exert an effect on GnRH secretion, we employed double labelled in situ hybridisation, with RNAScope, for co-localisation of the GLP-1 receptor (GLP-1R) in GnRH, Kisspeptin and NPY cells in the hypothalami of three ewes in the luteal phase of the estrous cycle. GLP1R expression was clearly visible but the receptor was not expressed in GNRH1 or NPY expressing neurons and was visualised in <5% of KISS1 expressing neurons. We conclude that GLP-1 may act at the level of the secretory terminals of GnRH neurons in the ME to stimulate GnRH secretion, the pathway through which such effect is manifested remains unknown.

Disparate effects of feeding on core body and adipose tissue temperatures in animals selectively bred for Nervous or Calm temperament.

In addition to homeostatic regulation of body mass, nonhomeostatic factors impact on energy balance. Herein we describe effects of temperament on adipose and core body temperatures in sheep. Animals were genetically selected for Nervous or Calm traits. We characterized the effects of 1) high- and low-energy intake and maintenance feeding, 2) meal anticipation, and 3) adrenocorticotropin challenge on core body and adipose temperatures. Temperature measurements (5 min) were made using a thermistor inserted into the carotid artery (core body) and a probe in the retroperitoneal fat. An imposed feeding window was used to establish postprandial elevations in temperature. Fat tissue was taken from retroperitoneal and subcutaneous regions for real-time PCR analyses. We demonstrate that innate differences in temperament impact on adipose and core body temperatures in response to various dietary and evocative stimuli. In response to homeostatic cues (low-energy intake and maintenance feeding) core body temperature tended to be higher in Calm compared with Nervous animals. In contrast, in response to nonhomeostatic cues, Nervous animals had higher anticipatory thermogenic responses than Calm animals. Expression of uncoupling protein (UCP)-1 and -2 mRNA were higher in retroperitoneal tissue than in subcutaneous tissue, but UCP3 and leptin mRNA levels were similar at both sites; expression of these genes was similar in Nervous and Calm animals. There were no differences in stress responsiveness. We conclude that temperament differentially influences adipose thermogenesis and the regulation of core body temperature in responses to both homeostatic and nonhomeostatic stimuli.

Targeting energy expenditure in muscle as a means of combating obesity.

1. To date, an effective therapeutic agent that induces weight loss in obese subjects remains elusive. In order to establish a successful means to combat obesity, it is imperative that we identify novel targets that regulate energy balance. 2. Exciting new data have created resurgence in interest in the role of thermogenesis in energy balance. Recently, it has been demonstrated that functional brown adipocytes are present in adult humans and that brown adipocytes and myocytes are derived from a similar cell lineage and are thus likely to have similar physiological functions. 3. Recent work in the sheep has demonstrated that diffuse fat beds and skeletal muscle exhibit thermogenic properties. Furthermore, in sheep, central administration of leptin markedly increases postprandial thermogenesis in both fat and muscle tissues. This demonstrates that thermogenic processes in skeletal muscle can be manipulated in a similar way to thermogenesis in brown fat. 4. Given that skeletal muscle comprises a significant portion of bodyweight, approximately 30-40% of total body mass, we predict that energy expended by this tissue is likely to have significant ramifications for the regulation of bodyweight. 5. We propose that manipulation of skeletal muscle thermogenesis may provide a novel avenue for the development of anti-obesity therapies.

Effect of sex and sex steroids on brown adipose tissue heat production in humans.

OBJECTIVE: Retrospective studies suggest that women have more active brown adipose tissue (BAT) than men, but little is known of the effect of fluctuating sex steroids across the menstrual cycle on thermogenesis in women. DESIGN: To characterise the effects of sex and sex steroids on BAT activity we recruited healthy weight men (n = 14) and women at two stages of the menstrual cycle (luteal, n = 9; follicular, n = 11). METHODS: Infrared thermography measured supraclavicular temperature to index BAT thermogenesis in response to both cold (immersion of one hand in water at 15°C) and meal (Ensure, 10 kcal/kg body weight) stimuli. RESULTS: Adaptive BAT temperature responses were greater (P < 0.05) in women than men, irrespective of stage of menstrual cycle. Whereas during cold exposure, the increase in BAT temperature was abrogated (P < 0.05) in women during follicular phase compared to men and women during luteal phase. Plasma concentrations of progesterone, 17ß-estradiol, testosterone and cortisol were measured. Regression analyses demonstrated that baseline BAT temperature was positively correlated (P < 0.05) with progesterone levels, but was inversely associated (P < 0.05) with cortisol concentration. Both cold- and meal-induced changes in BAT temperature mildly correlated (P = 0.07; P < 0.05) with 17ß-estradiol levels, but not with testosterone concentrations. CONCLUSIONS: Baseline supraclavicular temperature is elevated in women during the luteal phase of the menstrual cycle, which correlated with elevated progesterone concentrations. Women exhibited greater thermogenic responses than men, irrespective of the state of the menstrual cycle, which was associated with plasma levels of 17ß-estradiol. We conclude that sex steroids may regulate BAT thermogenesis in healthy adults.

Intranasal Targeting of Hypothalamic PTP1B and TCPTP Reinstates Leptin and Insulin Sensitivity and Promotes Weight Loss in Obesity.

The importance of hypothalamic leptin and insulin resistance in the development and maintenance of obesity remains unclear. The tyrosine phosphatases protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP) attenuate leptin and insulin signaling and are elevated in the hypothalami of obese mice. We report that elevated PTP1B and TCPTP antagonize hypothalamic leptin and insulin signaling and contribute to the maintenance of obesity. Deletion of PTP1B and TCPTP in the hypothalami of obese mice enhances CNS leptin and insulin sensitivity, represses feeding, and increases browning, to decrease adiposity and improve glucose metabolism. The daily intranasal administration of a PTP1B inhibitor, plus the glucocorticoid antagonist RU486 that decreases TCPTP expression, represses feeding, increases browning, promotes weight loss, and improves glucose metabolism in obese mice. Our findings causally link heightened hypothalamic PTP1B and TCPTP with leptin and insulin resistance and the maintenance of obesity and define a viable pharmacological approach by which to promote weight loss in obesity.

Profiling postprandial thermogenesis in muscle and fat of sheep and the central effect of leptin administration.

Brown adipose tissue thermogenesis is an important component of energy expenditure as exemplified in rodents. Other tissues such as white adipose tissue and muscle are also capable of thermogenesis, but regulation of heat production in these tissues is poorly understood. We used a relatively large animal model, the ovariectomized sheep, in which site-specific temperature measurements were made as an index of thermogenic output. Dataloggers were implanted into the retroperitoneal (visceral) fat, gluteal (sc) fat, and skeletal muscle of the hind limb, and were programmed to record temperature every 15 min. Animals (n = 4) were then placed on a feeding schedule (fed between 1100 and 1600 h) to entrain a postprandial response in thermogenesis. Baseline thermogenesis (0800-1100 h) was higher (P < 0.05) in visceral fat and muscle than in gluteal fat, whereas the amplitude of the postprandial increase was similar at all three sites. Intracerebroventricular infusion into the lateral ventricle of either vehicle (artificial cerebrospinal fluid) or leptin (10 microg/h at 100 microl/h) for 24 h (0900-0900) was performed in a cross-over design with a 1-wk recovery period between treatments. Central leptin infusion did not alter the basal thermogenic rate but markedly enhanced the postprandial response in both fat and muscle tissues. This was manifest by increased (P < 0.05) amplitude and duration of the postprandial thermogenic response, and the effect was greater in muscle and visceral fat than in gluteal fat. These data demonstrate that leptin is able to regulate thermogenesis in muscle, providing a novel target for the manipulation of energy balance.

Adipose and skeletal muscle thermogenesis: studies from large animals.

The balance between energy intake and energy expenditure establishes and preserves a 'set-point' body weight. The latter is comprised of three major components including metabolic rate, physical activity and thermogenesis. Thermogenesis is defined as the cellular dissipation of energy via heat production. This process has been extensively characterised in brown adipose tissue (BAT), wherein uncoupling protein 1 (UCP1) creates a proton leak across the inner mitochondrial membrane, diverting protons away from ATP synthesis and resulting in heat dissipation. In beige adipocytes and skeletal muscle, thermogenesis can occur independent of UCP1. Beige adipocytes have been shown to produce heat via UCP1 as well as via both futile creatine and calcium cycling pathways. On the other hand, the UCP1 homologue UCP3 is abundant in skeletal muscle and post-prandial thermogenesis has been associated with UCP3 and the futile calcium cycling. This review will focus on the differential contributions of adipose tissue and skeletal muscle in determining total thermogenic output and energy expenditure in large mammals. Sheep and pigs do not have a circumscribed brown fat depot but rather possess white fat depots that contain brown and beige adipocytes interspersed amongst white adipose tissue. This is representative of humans, where brown, beige and white adipocytes have been identified in the neck and supraclavicular regions. This review will describe the mechanisms of thermogenesis in pigs and sheep and the relative roles of skeletal muscle and adipose tissue thermogenesis in controlling body weight in larger mammals.

Continuous Kisspeptin Restores Luteinizing Hormone Pulsatility Following Cessation by a Neurokinin B Antagonist in Female Sheep.

Pulsatile secretion of the gonadotropin-releasing hormone (GnRH) drives pulsatile secretion of the luteinizing hormone (LH), with evidence that this depends on kisspeptin (Kiss) input to GnRH neurons. Kiss administration causes acute GnRH/LH secretion, and electrophysiological data suggest that Kiss neurons may act in a phasic manner to drive GnRH secretion, but there is not definitive evidence for this. The product of the Kiss-1 gene is proteolytically cleaved to smaller products, and the 10 amino acid C-terminal product (Kiss-10) displays full bioactivity. We have shown previously that continuous delivery of Kiss-10 to anestrous ewes can cause a surge in GnRH secretion and ovulation and increases LH pulse frequency in humans. Here, we tested the hypothesis that continuous Kiss-10 delivery can support pulsatile GnRH/LH secretion in the sheep. Neurokinin B (NKB) provides positive drive to Kiss neurons, so we therefore infused an NKB antagonist (ANT-08) intracerebroventricularly to induce cessation of pulsatile GnRH/LH secretion, with or without concomitant continuous Kiss-10 infusion. ANT-08 suppressed GnRH/LH pulsatility, which was immediately restored with continuous Kiss-10 infusion. These data support the notion that Kiss-10 action is downstream of NKB signaling and that continuous Kiss-10 stimulation of GnRH neurons is sufficient to support a pulsatile pattern of GnRH/LH secretion. This offers further support to the theory that GnRH pulse generation is intrinsic to GnRH neurons and that pulsatile GnRH release can be affected with continuous stimulation by Kiss-10.

Glycerol transport: an additional target for obesity therapy?

There is increasing evidence that the glycerol channel, aquaporin 7(AQP7), has an important role in adipose tissue formation and function--deletion of the gene in a mouse strain leads to obesity and diabetes type 2 if the mice are aged or fed earlier with a high-fat or sucrose diet. Can increased levels of AQP7 in adipose tissue protect against obesity? New studies on AQP7 highlight the important role of glycerol transport in the development of obesity and metabolic disease.