A redox system for brain targeted estrogen delivery causes chronic body weight decrease in rats

The effects of 2 redox based carriers for brain directed delivery of estradiol (CDS-E2) and ethinyl estradiol (CDS-EE) on body weight were examined in rats. A single dose of CDS-E2 (3 mg/kg) decreased weight gain in castrate rats for at least 24 days. The dose response of weight gain and LH suppression were compared 12 days and 12 to 25 after CDS-E2 and CDS-EE, respectively, in ovariectomized (OVX) rats. Weight decrease was detected at a lower dose and was significant for longer after drug treatment than LH decrease. Both compounds were more potent than equimolar estradiol or estradiol valerate in reducing weight gain. Intact rats also showed decreased weight gain but were less sensitive to CDS-E2 compared to OVX rats. The effects appeared to be estrogen specific as carrier-linked testosterone had no effect on weight. The mechanisms of sustained and potent drug effects on weight are being explored.     

Obestatin acts in brain to inhibit thirst

Derived from the same prohormone, obestatin has been reported to exert effects on food intake that oppose those of ghrelin. The obestatin receptor GPR39 is present in brain and pituitary gland. Since the gene encoding those two peptides is expressed also in those tissues, we examined further the possible actions of obestatin in vivo and in vitro. Intracerebroventricular administration of obestatin inhibited water drinking in ad libitum-fed and -watered rats, and in food-and water-deprived animals. The effects on water drinking preceded and were more pronounced than any effect on food intake, and did not appear to be the result of altered locomotor/behavioral activity. In addition, obestatin inhibited ANG II-induced water drinking in animals provided free access to water and food. Current-clamp recordings from cultured, subfornical organ neurons revealed significant effects of the peptide on membrane potential, suggesting this as a potential site of action. In pituitary cell cultures, log molar concentrations of obestatin ranging from 1.0 pM to 100 nM failed to alter basal growth hormone (GH) secretion. In addition, 100 nM obestatin failed to interfere with the stimulation of GH secretion by GH-releasing hormone or ghrelin and did not alter the inhibition by somatostatin in vitro. We conclude that obestatin does not act in pituitary gland to regulate GH secretion but may act in brain to alter thirst mechanisms. Importantly, in rats the effects of obestatin on food intake may be secondary to an action of the peptide to inhibit water drinking.     

Correlations linking hypophysis and epiphysis volumes to body weight and brain weight in Simian and in man]

The human hypophyseal and epiphyseal volumes are quantitatively conformable to those of the simians studied. In simians and man, the hypophysis is better correlated to body weight and to brain weight than the epiphysis, as already observed by us in other Mammals (Insectivora, Prosimiano, Rodents and Chiroptera). The pineal gland must be correlated to a non essential somatic function that varies from one species to another at constant somatic weight.     

Ceruletide acts in the abdomen, not in the brain, to produce satiety

Ceruletide (caerulein), a decapeptide extracted from the skin of the frog, Hyla caerulea, is very similar in structure to the C-terminal octapeptide of cholecystokinin (CCK-8). Although ceruletide and CCK-8 act through similar or identical receptors to produce the same visceral effects, previous studies in the rat suggested that peripherally administered ceruletide acted directly on the ventromedial hypothalamic (VMH) area to decrease food intake, but peripherally administered CCK-8 acted at a vagally innervated abdominal site to decrease food intake. Since it is unprecedented for these two peptides to produce the same effect by acting at different sites, we investigated the site of action of ceruletide's satiety effect in the rat and compared it to the site of action of CCK-8. The major results were: (1) intraperitoneal administration of ceruletide and CCK-8 inhibited food intake, but intraventricular administration did not; (2) the satiety effect of ceruletide and CCK-8 was not changed by bilateral lesions of the VMH; and (3) the satiety effect of ceruletide and CCK-8 was abolished or markedly reduced by bilateral abdominal vagotomy. We conclude that ceruletide acts at the same vagally innervated abdominal site to produce satiety as CCK-8 does and that neither peptide acts directly on the VMH area.     

Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats

Findings from our laboratory and others have demonstrated that the hormone insulin has chronic effects within the CNS to regulate energy homeostasis and to decrease brain reward function. In this study, we compared the acute action of insulin to decrease intake of a palatable food in two different behavioral tasks-progressive ratios sucrose self-administration and micro opioid-stimulated sucrose feeding-when administered into several insulin-receptive sites of the CNS. We tested insulin efficacy within the medial hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, the nucleus accumbens, and the ventral tegmental area. Administration of insulin at a dose that has no chronic effect on body weight (5 mU) into the ARC significantly suppressed sucrose self-administration (75+/-5% of paired control). However, although the mu opioid DAMGO, [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin acetate salt, stimulated sucrose intake at all four CNS sites, the ventral tegmental area was the only sensitive site for a direct effect of insulin to antagonize acute (60 min) micro opioid-stimulated sucrose feeding: sucrose intake was 53+/-8% of DAMGO-induced feeding, when insulin was coadministered with DAMGO. These findings demonstrate that free feeding of sucrose, and motivated work for sucrose, can be modulated within unique sites of the CNS reward circuitry. Further, they support the interpretation that adiposity signals, such as insulin, can decrease different aspects of ingestion of a palatable food, such as sucrose, in an anatomically specific manner.     

Gender differences in predictors of body weight and body weight change in healthy adults

Background: Overweight and obesity are important predictors of a wide variety of health problems. Analysis of naturally occurring changes in body weight can provide valuable insights in improving our understanding of the influence of demographic, lifestyle, and psychosocial factors on weight gain in middle‐age adults. Objective: To identify gender‐specific predictors of body weight using cross‐sectional and longitudinal analyses. Methods and Procedures: Anthropometric, lifestyle and psychosocial factors were measured at baseline and then quarterly for 1 year in 572 healthy adult volunteers from Central Massachusetts who were recruited between 1994 and 1998. Linear mixed models were used to analyze the relationship between body weight and potential predictors, including demographic (e.g., age, educational level), lifestyle (e.g., diet, physical activity, smoking), and psychosocial (e.g., anxiety, depression) factors. Results: Over the 1‐year study period, on average, men gained 0.3 kg and women lost 0.2 kg. Predictors of lower body weight at baseline in both men and women included current cigarette smoking, greater leisure‐time physical activity, and lower depression and anxiety scores. Lower body weights were associated with a lower percentage of caloric intake from protein and greater occupational physical activity levels only among men; and with higher education level only among women. Longitudinal predictors of 1‐year weight gain among women included increased total caloric intake and decreased leisure‐time physical activity, and among men, greater anxiety scores. Discussion: Demographic, lifestyle and psychosocial factors are independently related to naturally occurring changes in body weight and have marked differential gender effects. These effects should be taken into consideration when designing interventions for weight‐loss and maintenance at the individual and population levels.     

Reductions in total body fat decrease humoral immunity

Mounting an immune response requires substantial energy, and it is well known that marked reductions in energy availability (e.g. starvation) can suppress immune function, thus increasing disease susceptibility and compromising survival. We tested the hypothesis that moderate reductions in energy availability impair humoral immunity. Specifically, we examined the effects of partial lipectomy (LIPx) on humoral immunity in two seasonally breeding rodent species, prairie voles (Microtus ochrogaster) and Siberian hamsters (Phodopus sungorus). Animals received bilateral surgical removal of epididymal white adipose tissue (EWATx), inguinal white adipose tissue (IWATx) or sham surgeries and were injected with the antigen keyhole limpet haemocyanin (KLH) either four or 12 weeks after surgery. In prairie voles, serum anti-KLH immunoglobulin G (IgG) did not differ significantly at four weeks. At 12 weeks, serum IgG was significantly reduced in IWATx, but not EWATx animals, compared with sham-operated animals. In Siberian hamsters, both IWATx and EWATx animals reduced serum IgG at four weeks. At 12 weeks, EWATx hamsters displayed a significant compensatory increase in IWAT pad mass compared with sham-operated hamsters, and serum IgG no longer differed from sham-operated animals. There was no significant increase in EWAT in IWATx hamsters compared with sham animals and IgG remained significantly reduced in IWATx hamsters. These results suggest that reductions in energy availability can impair humoral immunity.     

Pentagastrin in the circulation acts directly on the brain to depress motility of the stomach in sheep

The mechanism whereby pentagastrin inhibits the frequency of contractions of the reticulo-rumen in conscious sheep was studied by comparing the effects of a range of doses given by continuous infusion into the jugular vein and the carotid artery. The intracarotid infusions at rates of 1 and 2 μg/kg per h were more effective than the jugular infusions $\text{(P < 0.05)}$. This is the first report that pentagastrin administered intravenously acts directly on the brain to alter the motility of a portion of the digestive tract. This agrees with the fact that in sheep and other ruminants, the gastric centres in the medulla dictate the frequency of cyclical motility in the reticulum.     

Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight

Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1-56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.     

On the assessment of body weight

Body height-weight indices are useful for determining body bulk and of these Rohrer's body bulk index (weight divided by the cube of the body height) is the only one that has a theoretically acceptable base. The statistical analysis of data on 747 healthy men and women and comparison with empirical ideal weights also showed this index to be the most suitable. A nomogram for its graphical determination is therefore added.Indices are not all necessary for the determination of overweight or underweight; it is preferable to orientate the assessment on heightspecific ideal weights. Broca's rule for the determination of ideal weights is groundless and supplies unsatisfactory results. The ideal weights based on the criterion of length of life elicited by the Metropolitan Life Insurance Company are preferable. Nomograms for these weight norms are given which permit direct determination of the absolute and percentual deviation from the ideal norm.     

Evidence dromyosuppressin acts at posterior and anterior pacemakers to decrease the fast and the slow cardiac activity in the blowfly Protophormia terraenovae

The molecular complexity of the simple blowfly heart makes it an attractive preparation to delineate cardiovascular mechanisms. Blowfly cardiac activity consists of a fast, high-frequency signal phase alternating with a slow, low-frequency signal phase triggered by pacemakers located in the posterior abdominal heart and anterior thoracocephalic aorta, respectively. Mechanisms underlying FMRFamide-related peptides (FaRPs) effects on heart contractions are not well understood. Here, we report antisera generated to a FaRP, dromyosuppressin (DMS, TDVDHVFLRFamide), recognized neuronal processes that innervated the blowfly Protophormia terraenovae heart and aorta. Dromyosuppressin caused a reversible cardiac arrest. High- and low-frequency signals were abolished after which they resumed; however, the concentration-dependent resumption of the fast phase differed from the slow phase. Dromyosuppressin decreased the frequency of cardiac activity in a dose-dependent manner with threshold values between 5 fM and 0.5 fM (fast phase), and 0.5 fM and 0.1 fM (slow phase). Dromyosuppressin structure-activity relationship (SAR) for the decrease of the fast-phase frequency was not the same as the SAR for the decrease of the slow-phase frequency. The alanyl-substituted analog TDVDHVFLAFamide ([Ala9] DMS) was inactive on the fast phase, but active on the slow phase, a novel finding. FaRPs including myosuppressins are reported to require the C-terminal RFamide for activity. Our data are consistent with the conclusions DMS acts on posterior and anterior cardiac tissue to play a role in regulating the fast and slow phases of cardiac activity, respectively, and ligand-receptor binding requirements of the abdominal and thoracocephalic pacemakers are different.     

Development of body weight in the Norwegian population

In Norwegian adult men, body mass index (BMI) increased from around 25 kg/m(2) in the late 1960s to around 26.5 kg/m(2) in the late 1990s, and the prevalence of obesity increased from about 5% to 15% in the same period. In women the prevalence of obesity actually decreased from around 13% in the late 1960s to 7% in the late 1980s. However, during the last years the prevalence has also increased reaching about 13% in the late 1990s. It is important to note that both mean and median BMI has increased with a shift in the distribution to the right. The proportion of normal weight individuals has thus decreased, whereas the proportion of obese has increased. The increase in BMI has occurred in different age groups. Although obesity is associated with low education and a sedentary lifestyle, the increase in BMI has also occurred in the more educated and physical active.