The hypothalamic-pituitary-adrenal-axis in the regulation of energy balance

Human (visceral) obesity is associated with alterations hypothalamus–pituitary–adrenal (HPA) axis functioning. It is however not completely clear whether the HPA axis is causally or co-incidentally related to (visceral) obesity. This review summarizes supporting data of an involvement of the HPA axis in the development of (visceral) obesity. First, several DNA polymorphisms related to HPA axis functioning are correlated to the development of obesity. Second, chronic elevation of circulatory glucocorticoid concentrations, as in Cushing's disease, results in increased abdominal adiposity. Third, (visceral) obesity is associated with a diminished capacity of cortisol to suppress its own secretion. HPA axis functioning might affect energy balance through affecting energy intake. Both CRH and cortisol influence physiological, central mechanisms involved in the regulation of food intake. Still, general activation of the HPA axis has shown to have inconsistent effects on food intake in humans. This inconsistency may partially be explained by gender differences, individual differences in the functioning of the HPA axis, as well as differences in attitude towards eating. In particular, women with high scores on dietary restraint are prone to stress-induced hyperphagia. Dietary restraint scores, in turn, are positively correlated to basal and dexamethasone-suppressed cortisol levels, indicating a complex dual relationship between stress, HPA axis functioning, attitude towards eating and the risk for stress-induced hyperphagia. In the Western society, with chronically high ambient levels of stress and the availability of high caloric foods, this relationship may imply a risk for the development of (visceral) obesity and the metabolic syndrome.     

The effects of gonadectomy on the sex differences in dietary self-selection patterns and carcass compositions of rats

The relationship of dietary self-selection patterns and carcass composition was studied in intact and gonadectomized male and female rats. Males consumed a significantly greater proportion of their diets as protein and had a greater proportion of their carcasses as fat than females. Gonadectomy increased the percentage protein selected by females to the level of intact males and altered the proportions of the carcass tissues to the levels of these males. The results were discussed in terms of the regulatory consequences of varying nutritional intake patterns and the role of female sex hormones in the regulation of body weight and composition.     

长期高脂饮食对大鼠下丘脑腹内侧核、弓状核PGC-1α表达的影响

目的　观察高脂饮食对下丘脑腹内侧核、弓状核PGC-1α表达的影响。 方法 SD大鼠随机分为正常饮食组及高脂饮食组,喂养8周后,采用HE染色法观察肝脏组织脂肪变性情况,采用免疫荧光化学法染色,观察PGC-1α在下丘脑腹内侧核、弓状核的表达变化。 结果 8周后正常饮食组大鼠肝组织的肝索排列整齐,肝索、肝血窦、肝细胞之间均界限分明,细胞核清晰,胞浆均匀,未见肝细胞脂变和坏死;而摄取高脂饮食的大鼠的肝脏组织表现为肝索排列紊乱、肝血窦腔隙极小、细胞界限不清、肝细胞肿胀,胞浆中出现了大小不等的脂肪空泡,有严重脂肪变性特征。正常饮食大鼠下丘脑腹内侧核测定区域面积下PGC-1α的细胞数为199.96±42.95,高脂饮食大鼠腹内侧核PGC-1α的细胞数为(256.08±39.25),二者具有统计差异P<0.05;正常饮食大鼠弓状核PGC-1α的细胞数为(173.25±47.19),高脂饮食大鼠弓状核PGC-1α的细胞数为(200.48±51.44),二者具有统计差异P<0.05。 结论 高脂饮食导致下丘脑腹内侧核、弓状核PGC-1α表达增高,可能与能量代谢平衡调节功能有关。     

Some effects of ovariectomy and estrogen replacement on body composition in the rat

Sprague-Dawley rats were ovariectomized (OvX) at 3 ages, day 2 (D2), week 4 (W4) and week 7 (W7); a group of OvX W7 rats were treated daily with estrogen (OB; 2 μg for 2 or 5 weeks from 10 weeks of age). Rats were slaughtered at 4 ages, weeks 7, 9, 12 and 15, for the chemical analysis of carcass and skin. Chemical compositions were analysed as % wet weight and as component weights by two-way analysis of variance. Component weights were also analysed by allometry, regressing against nose-anal length. Ovariectomy increased overall body weight without causing obesity. The weight gain of the OvX rat was mainly a true growth response but OvX affected body proportions so that at a given body length the OvX rat had a larger skin and carcass than controls. Ovariectomy at the earliest age (D2) produced the smallest response in body weight and body length but produced the greatest fat redistribution towards the skin and away from the carcass; there was no net change in whole body fat levels following OvX. Long-term daily OB treatment increased fat reserves but slowed the growth of other body components, including the axial skeleton. Whereas OvX redistributed components between skin and carcass, OB treatment reversed this process.     

Metabolic sensing neurons and the control of energy homeostasis

The brain and periphery carry on a constant conversation; the periphery informs the brain about its metabolic needs and the brain provides for these needs through its control of somatomotor, autonomic and neurohumoral pathways involved in energy intake, expenditure and storage. Metabolic sensing neurons are the integrators of a variety of metabolic, humoral and neural inputs from the periphery. Such neurons, originally called "glucosensing", also respond to fatty acids, hormones and metabolites from the periphery. They are integrated within neural pathways involved in the regulation of energy homeostasis. Unlike most neurons, they utilize glucose and other metabolites as signaling molecules to regulate their membrane potential and firing rate. For glucosensing neurons, glucokinase acts as the rate-limiting step in glucosensing while the pathways that mediate responses to metabolites like lactate, ketone bodies and fatty acids are less well characterized. Many metabolic sensing neurons also respond to insulin and leptin and other peripheral hormones and receive neural inputs from peripheral organs. Each set of afferent signals arrives with different temporal profiles and by different routes and these inputs are summated at the level of the membrane potential to produce a given neural firing pattern. In some obese individuals, the relative sensitivity of metabolic sensing neurons to various peripheral inputs is genetically reduced. This may provide one mechanism underlying their propensity to become obese when exposed to diets high in fat and caloric density. Thus, metabolic sensing neurons may provide a potential therapeutic target for the treatment of obesity.     

Relative contribution of aging and menopause to changes in lean and fat mass in segmental regions

Objective: The aim of the study was to investigate the relative contribution of aging and menopause to the changes in lean and fat mass in segmental regions. Materials and methods: Subjects were 365 pre- and 201 postmenopausal Japanese women aged between 20 and 70 years old. Age, height, weight, body mass index (BMI, Wt/Ht²), age at menopause, years since menopause (YSM), and menopausal status were recorded. Lean and fat mass of the arms, trunk, legs, total body, and the ratio of trunk fat mass to leg fat mass amount (trunk–leg fat ratio) were measured by dual-energy X-ray absorptiometry (DEXA). Regional (arms, lumbar spine, pelvis, legs, and total body) bone mineral density (BMD) were measured by DEXA. Results: Total body lean mass and regional BMD decreased (P<0.001), while percentage of body fat, trunk fat mass, and trunk–leg fat ratio increased (P<0.001) with aging and after menopause. On multiple regression analyses, trunk and total body lean mass were inversely correlated with menopausal status (P<0.001 and 0.05, respectively) but not with age. Trunk fat mass, trunk–leg fat ratio, and percentage of body fat were positively correlated with age (P<0.01) but not with menopausal status. Regional BMD were more inversely correlated with menopausal status (P<0.001) than age. Conclusion: Decrease in lean mass and BMD are more menopause-related, while the shift toward upper body fat distribution and overall adiposity are more age-related. Lean tissue is similar to bone tissue from the viewpoint of more undergoing menopausal effect.     

Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice

The objective of the present study was to investigate the effects of the antiepileptic drug topiramate (TPM) on components of energy balance in lean and obese (ob/ob) mice in the presence or absence of leptin. Lean and ob/ob mice infused with either leptin or phosphate-buffered saline were treated with TPM for 7 days. TPM was mixed into the diet and administered at a dose of 60 mg/kg/day, whereas leptin was infused at the rate of 100 microg/kg/day using osmotic minipumps, which were subcutaneously implanted in the interscapular region. Food intake and body weight were monitored throughout the study. Body composition was measured prior to and following treatment with TPM and leptin, using dual-energy X-ray absorptiometry (DEXA). Glucose (glucose oxidase method) and insulin (radioimmunoassay) were also determined. TPM and leptin significantly reduced body weight gain, food intake and body fat gain in obese mice. The effects of TPM and leptin on fat gain were also statistically significant in lean animals. There was no interaction of TPM and leptin on the energy balance variables, the effects of the two substances being additive instead. Leptin abrogated hyperinsulinemia in obese mutants whereas TPM did not alter insulin levels in either lean or obese mice. The combination of leptin and TPM led to the normalization of glucose levels in obese mice. Our study demonstrates an effect of TPM in leptin-deficient animals, which suggests that TPM does not require the presence of leptin to exert its effect. They also show that the effects of leptin and TPM can be additive. The treatment with leptin in ob/ob mice neither accentuated nor blunted the effect of TPM on energy balance.     

Sex differences in the regulation of body weight

Obesity and its associated health disorders and costs are increasing. Males and females differ in terms of how and where body fat is stored, the hormones they secrete in proportion to their fat, and the way their brains respond to signals that regulate body fat. Fat accumulation in the intra-abdominal adipose depot is associated with the risk for developing cardiovascular problems, type-2 diabetes mellitus, certain cancers and other disorders. Men and postmenopausal women accumulate more fat in the intra-abdominal depot than do pre-menopausal women, and therefore have a greater risk of developing metabolic complications associated with obesity. The goal of this review is to explore what we know about sexual dimorphisms in adipose tissue accrual and deposition. Elucidating the mechanisms by which sex hormones may modulate the way in which fat is accumulated and stored is a critical area of research due to the prevalence of obesity and the metabolic syndrome, and the rapid increase in propensity for these diseases following menopause.     

Relations between anthropometric characteristics and degree of severity of the climacteric syndrome in Austrian women

The connection between body-shape characteristics, namely distribution of subcutaneous fat, and the occurrence of psychic and somatic climacteric symptoms was investigated in 142 postmenopausal women from Eastern Austria. It was found that both psychic and somatic symptoms are significantly related to body-shape characteristics. With increasing breadth and circumference, i.e. a higher proportion of subcutaneous fat, the degree of severity of several symptoms increases, with the exception of hot flushes and sweating, dizziness, headache and palpitation. Since, in the climacteric, subcutaneous fat has a positive impact on the secretion of oestrogens and thus on climacteric symptoms, the results of the present study may be interpreted as an effect of the psychosocial stress to which corpulent women are exposed in our society because they do not fit the beauty ideal typical of our culture.     

Influence of early dietary experience on energy regulation in rats

The environmental mechanisms that have contributed to the rapid increases in overweight and obesity in the US over the past 25-30 years have yet to be fully specified. One hypothesis that has been forwarded is that increased consumption of calories in liquid form may be a contributing factor, since some studies support the idea that caloric compensation is less adequate for liquid calories compared to calories delivered in more solid form. Work from our laboratory using rats has examined the role that differences in diet viscosity may play in altering energy intake and body weight regulation. This work has suggested that when offered diets matched on caloric density, macronutrient and micronutrient composition, and differing only in viscosity, adult rats fail to compensate for calories delivered in low-viscosity form in short-term intake tests. Further, long-term consumption of low-viscosity diets leads to enhanced weight gain in adult rats. In the present studies, we examined whether short- or long-term exposure to varying relationships between viscosity and calories led to altered food intake or body weight regulation in juvenile rats. The results demonstrated that animals given either short- or long-term experience with direct relationships between viscosity and calories (high viscosity, high calorie meals and low viscosity, low calorie meals) did not differ in food intake or body weight gain compared to animals given short- or long-term experience with indirect relationships between viscosity and calories (high viscosity, low calorie meals and low viscosity, high calorie meals). When juvenile rats were given long-term (9 weeks) exposure to a single, high or low viscosity diet supplement, matched on caloric density and differing only in viscosity, there were no effects on body weight gain. However, analysis of body composition using DEXA demonstrated that animals consuming the low viscosity supplements had significantly greater body fat than animals that consumed either the high viscosity supplement or no dietary supplement at all. These differences in body fat persisted for at least 3 months following the cessation of dietary supplements; during this 3-month period, animals previously exposed to the low viscosity supplement also gained significantly more weight than animals previously exposed to the high viscosity supplement. Taken together, the results suggest that consuming calories in low viscosity form may contribute to poor intake regulation over the short-term and to increased adiposity over the long term. When animals experience these diets as juveniles, these effects may persist into adulthood.     

The effect of prior exercise on oral glucose tolerance in late gestational women

Summary Glucose tolerance deteriorates over the course of a normal human pregnancy as a result of increased peripheral insulin resistance. In contrast, physical exercise has been shown to improve glucose tolerance and blunt the insulin response to a glucose load in insulin-resistant individuals. The purpose of this study was to determine the effect of exercise on glucose tolerance and the insulin response in healthy women during the third trimester of pregnancy (33 weeks of gestation). Five subjects underwent oral glucose tolerance tests (a) 30 min following a 30-min exercise bout on a cycle ergometer at a relative intensity of 50% maximal aerobic capacity, and (b) on a control day without prior exercise. The area under the glucose concentration curve was not different between trials, while the area under the insulin concentration curve was decreased by 23% in the exercise trial compared with the control trial (P < 0.05). These results suggest that the insulin response to a glucose load is improved in late gestational women by a single bout of moderate intensity exercise.     

Control of energy homeostasis by insulin and leptin: Targeting the arcuate nucleus and beyond

As the obesity epidemic, diabetes mellitus type 2, and associated comorbidities show no signs of abating, large efforts have been put into a better understanding of the homeostatic control mechanisms involved in regulation of body weight and energy homeostasis. For decades, the hypothalamic arcuate nucleus (ARC), which integrates peripheral signals and modulates appetite and metabolism, has been the focus of investigation. Besides these basic homeostatic circuits, food palatability and reward are thought to be major factors involved in the regulation of food intake. Highly palatable food is easily available, and is ingested even when there is no metabolic need for it. Thus, overriding of the homeostatic control systems by the cognitive, rewarding, social, and emotional aspects of palatable food may contribute to the obesity epidemic. This review aims to provide an updated view, how insulin and leptin as signals originating from the periphery of the body and communicating energy availability to the CNS act not only on ARC neurons, but also directly control the activity of neuronal circuits in control of food-associated reward mechanisms.     

The effect of leptin on feeding-regulating neurons in the rat hypothalamus.

Intense immunoreactivity for the leptin receptor was detected in the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMH), and lateral hypothalamus (LH) by immunohistochemistry. Cytosolic Ca2+ concentration ([Ca2+]i) in single neurons isolated from the ARC, VMH and LH was measured with dual wavelength fura-2 fluorescence imaging. A reduction of the superfusate glucose concentration from 10 to 1 mM increased [Ca2+]i in 21% of ARC neurons and 22% of LH neurons. Leptin at 0.1 nM inhibited the [Ca2+]i increase in 66 and 64% of these glucose-sensitive ARC and LH neurons, respectively. Inversely, 10 mM glucose increased [Ca2+]i in 49% of the VMH neurons, and 0.1 nM leptin at 1 mM glucose also increased [Ca2+]i in 84% of these glucose-responsive neurons. These results reveal that leptin inhibits the ARC and LH neurons and stimulates the VMH neurons via the leptin receptor expressed in these cells.     

The role of CCK2 receptors in energy homeostasis: insights from the CCK2 receptor-deficient mouse

The present study explored the contribution of type 2 cholecystokinin (CCK) receptors in energy regulation. A total of 78 CCK2 receptor-deficient mice and 80 wild-type controls were acclimated to a 12:12 light-dark cycle at 30 +/- 1 degrees C. Using a computer-monitored biotelemetry system, circadian patterns of body temperature, food intake, and activity were monitored for 4 days. Body weight and water consumption were manually recorded during this period. Results indicate that CCK2 receptor invalidation produces elevated body temperature during both the photophase and scotophase (by 0.38 and 0.12 degrees C, respectively), increased body weight (29.3 +/- 0.2 vs. 26.8 +/- 0.2 g) and water consumption (4.1 +/- 0.1 vs. 3.2 +/- 0.1 ml), and decreased scotophase locomotor activity (WT: 7.0 +/- 0.2 vs. KO: 6.1 +/- 0.2 counts/min). These findings suggest an important role for CCK2 receptors in processes underlying energy regulation during basal and possibly pathological states.     

Failure to demonstrate early metabolic changes in weanling growth-retarded hypophagic rats with lesions in the dorsomedial hypothalamic nuclei

Experiment 1: Weanling male rats received bilateral electrolytic lesions in the dorsomedial hypothalamic nuclei (DMNL rats); sham-operated animals served as controls. Rats were killed four hours and three and seven days postoperatively (post-op). Plasma was obtained and epididymal fat pads, diaphragm and liver aliquots were harvested and the in vitro incorporation of U-14C-glucose into CO2, glycogen, lipid and saponifiable fatty acids (FAs) were measured. Body weight, carcass lipid and food intake were significantly lower in DMNL rats than in controls. The only significant lesion-induced metabolic changes were hypoglycemia and greater tracer incorporation into epididymal fat pad lipid and diaphragm glycogen. Both DMNL rats and controls showed similar time courses of tracer incorporation into epididymal CO2 and FAs, diaphragm lipid and liver CO2, glycogen, lipid and FAs. Lesioned rats also showed more pronounced decreases of tracer incorporation from day 0 to day 3 in epididymal glycogen and lipid and diaphragm CO2 and glycogen. These data make it appear unlikely that very early deficits in glucose metabolism are the cause of the growth retardation seen in long-term studies with DMNL rats. The data also demonstrate considerable locus specificity, since weanling rats with ventromedial hypothalamic lesions (VMNL rats) in similar short-term studies have shown dramatic alterations in the above parameters. Experiment 2: Weanling DMNL rats and sham-operated rats were injected via tail vein with tritiated water one hour post-op. One hour after the injection they were decapitated. There were no significant differences between DMNL rats and controls in mumoles tritiated water incorporated into total liver, grams liver tissue, mg liver glycogen and ml or mg plasma glucose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Subtype specific roles of serotonin receptors in the spine formation of cortical neurons in vitro

Dendritic spines are postsynaptic structures which are formed from filopodia. We examined roles of serotonin (5-HT) receptors in the spine formation. Embryonic rat cortical neurons were cultured for 10 or 14 days and treated by 5-HT receptor agonists for 24 h. At 11 days in vitro, 5-HT_1A agonist increased filopodia density, whereas 5-HT_2A/2C agonist increased the density of puncta and spines. At 15 days in vitro, 5-HT_1A agonist decreased the density of puncta and spines, whereas 5-HT_2A/2C agonist decreased filopodia density with increase of spines. In conclusion, the present study shows 5-HT receptors have subtype-specific effects on the spine formation.     

Absence of weight regulation in exercising hamsters

Spontaneous activity on horizontal discs causes a permanent upward displacement of hamster weight, length, and, under some circumstances, percentage body fat. This phenomenon manifests itself through an immediate increase in the rate of weight gain, a disappearance of a preference for sunflower seeds, as well as in a delayed and gradual increase in food intake during and immediately following the activity period. A week after termination of spontaneous disc running normal regulation of body weight is reinstated and maintained at the new elevated weight level. These results suggest that some concomitant of spontaneous disc running in hamsters renders the weight-regulatory mechanisms inoperative.     

Effects of ovariectomy and estradiol on body weight and food intake in gold thioglucose-treated mice

Two experiments investigated the effects of ovariectomy and estradiol replacement on the body weight and food intake of mice that had previously been treated with either gold thioglucose or saline. Ovariectomy and estradiol benzoate injections altered food intake in gold thioglucose-treated mice as much as in saline controls. Ovariectomy increased body weight in saline controls but it was without effect on the body weight of gold thioglucose-treated mice.     

The role of neuropeptide W in energy homeostasis

Neuropeptide W is the endogenous ligand for G‐protein‐coupled receptors GPR7 and GPR8. In this review, we summarize findings on the distribution of neuropeptide W and its receptors in the central nervous system and the periphery, and discuss the role of NPW in food intake and energy homeostasis.