Weight loss after laparoscopic adjustable gastric band and resolution of the metabolic syndrome and its components.

BACKGROUND: Substantial weight loss in the setting of obesity has considerable metabolic benefits. Yet some studies have shown improvements in obesity-related metabolic comorbidities with more modest weight loss. By closely monitoring patients undergoing bariatric surgery, we aimed to determine the effects of weight loss on the metabolic syndrome and its components and determine the weight loss required for their resolution. METHODS: We performed a prospective observational study of obese participants with metabolic syndrome (Adult Treatment Panel III criteria) who underwent laparoscopic adjustable gastric banding. Participants were assessed for all criteria of the metabolic syndrome monthly for the first 9 months, then 3-monthly until 24 months. RESULTS: There were 89 participants with adequate longitudinal data. Baseline body mass index was 42.4±6.2 kg m-2 with an average age was 48.2±10.7 years. There were 56 (63%) women. Resolution of the metabolic syndrome occurred in 60 of the 89 participants (67%) at 12 months and 60 of the 75 participants (80%) at 24 months. The mean weight loss when metabolic syndrome resolved was 10.9±7.7% total body weight loss (TBWL). The median weight loss at which prevalence of disease halved was 7.0% TBWL (17.5% excess weight loss (EWL)) for hypertriglyceridaemia; 11% TBWL (26.1-28% EWL) for high-density lipoprotein cholesterol and hyperglycaemia; 20% TBWL (59.5% EWL) for hypertension and 29% TBWL (73.3% EWL) for waist circumference. The odds ratio for resolution of the metabolic syndrome with 10-12.5% TBWL was 2.09 (P=0.025), with increasing probability of resolution with more substantial weight loss. CONCLUSIONS: In obese participants with metabolic syndrome, a weight loss target of 10-12.5% TBWL (25-30% EWL) is a reasonable initial goal associated with significant odds of having metabolic benefits. If minimal improvements are seen with this initial target, additional weight loss substantially increases the probability of resolution.

The role of pharmacotherapy in the prevention and treatment of paediatric metabolic syndrome--Implications for long-term health: part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.

The metabolic syndrome (MetS) is defined as a clustering of risk factors predisposing to the future development of cardiovascular disease and Type 2 diabetes mellitus (T2DM). Its clinical relevance, above and beyond recognition and treatment of each of the component parts, is still hotly debated--especially within paediatric medicine. Prevention and treatment strategies for adult MetS focus on weight management, as obesity and insulin resistance are known to be at the central axis of the definition, alongside pharmacotherapy of integrally linked conditions such as hypertension and dyslipidaemia. In children and adolescents, however, opportunities for pharmacotherapy are currently limited and interventions aimed at weight management remain the sole treatment paradigm in the majority of cases. This is primarily due to a lack of long-term data relating to the degree of cardiovascular disease and T2DM risk from paediatric MetS, as well as concerns relating to safety and side effect profiles of currently available pharmacotherapies in those who are still growing and developing. Coupled with continuing concern about the recently recognised adverse effects of past and proposed anti-obesity drugs, this indicates that a new era of pharmacotherapy for paediatric MetS is unlikely to be imminent. In fact, the overall paucity of effective current interventions for paediatric MetS is concerning, especially given the fact that approximately 25-33% of all obese paediatric patients likely harbour the condition. It is therefore essential at the present time to concentrate efforts on properly testing the safety and efficacy of currently available products in well-constructed randomised controlled trials in obese adolescents. However, not all obese children and adolescents appear equally at-risk of long-term, weight-related morbidity and a change in emphasis is possibly warranted--one that moves away from simple weight reduction for all and more to a model of reducing long-term risk of cardiovascular disease and T2DM in those at greatest metabolic risk.

Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat.

Energy stores are held relatively constant in many mammals. The circuitry necessary for maintaining energy homeostasis should (1) sense the amount of energy stored in adipose tissue, (2) sense and integrate the multiple opposing signals regarding nutritional state, and (3) provide output regulating energy intake and expenditure to maintain energy homeostasis. We demonstrate that individual neurons within the paraventricular nucleus of the hypothalamus (PVH) are capable of detection and integration of orexigenic (neuropeptide Y [NPY]) and anorexigenic (melanocortin) signals, that NPY and melanocortins are functional antagonists of each other within the PVH in the regulation of feeding behavior, and that melanocortin administration within the PVH regulates both feeding behavior and energy expenditure. These data provide a cellular basis for the adipostat within neurons in the PVH that appear to be jointly regulated by NPY- and melanocortin-responsive neurons.

Short-term high-fat diet increases the presence of astrocytes in the hypothalamus of C57BL6 mice without altering leptin sensitivity.

Diet-induced obesity is associated with hypothalamic inflammation and this phenomenon has been proposed to explain leptin resistance. In the present study, we used a short-term high-fat diet (HFD) paradigm for 10 days and analysed the cellular and physiological responses to leptin administration in C57BL6 mice. In parallel, we performed glial fibrillary acidic protein immunostaining to measure the presence of astrocytes in the arcuate nucleus of the hypothalamus (ARH) after 10 days and 20 weeks of HFD. Interestingly, the results obtained demonstrate that the presence of star-like astrocytes is significantly increased after 10 days of HFD, although this is not associated with the absence of cellular and physiological response to leptin administration in mice. Taken together, the results of the present study suggest that star-like astrocytes rapidly increase in numbers in the ARH in response to HFD, although this phenomenon cannot explain the development of leptin resistance by itself.

Neuropeptide Y Y5 receptor protein in the cortical/limbic system and brainstem of the rat: expression on gamma-aminobutyric acid and corticotropin-releasing hormone neurons.

Neuropeptide Y displays diverse modes of action in the CNS including the modulation of cortical/limbic function. Some of these physiological actions have been at least partially attributed to actions of neuropeptide Y on the Y5 receptor subtype. We utilized an antibody raised against the Y5 receptor to characterize the distribution of this receptor subtype in the rat cortical/limbic system and brainstem. Y5-like immunoreactivity was located primarily in neuronal cell bodies and proximal dendritic processes throughout the brain. In the cortex, Y5 immunoreactivity was limited to a subpopulation of small gamma-aminobutyric-acid interneurons (approximately 15 microm diameter) scattered throughout all cortical levels. Double label immunofluorescence was also used to demonstrate that all of the Y5 immunoreactive neurons in the cortex displayed intense corticotropin releasing hormone immunoreactivity. The most intense Y5 immunoreactive staining in the hippocampus was located in the pyramidal cell layer of the small CA2 subregion and the fasciola cinerea, with lower levels of staining in the hilar region of the dentate gyrus and CA3 subregion of the pyramidal cell layer. Nearly all of the Y5 immunoreactive neurons in the hilar region of the hippocampus displayed gamma-aminobutyric-acid immunoreactivity. In the brainstem, Y5 immunoreactivity was most intense in the Edinger-Westphal nucleus, locus coeruleus and the mesencephalic trigeminal nucleus. The present study provides neuroanatomical evidence for the possible sites of action of the neuropeptide Y/Y5 receptor system in the control of cortical/limbic function. The presence of Y5 immunoreactivity on cell bodies and proximal dendritic processes in specific regions of the hippocampus suggests that this receptor functions to modulate postsynaptic activity. These data also suggest that the neuropeptide Y/Y5 system may play a role in the modulation of a specific population of GABAergic neurons in the cortex, namely those that contain corticotropin-releasing hormone. The location of the Y5 receptor immunoreactivity fits with the known physiological actions of neuropeptide Y and this receptor.

Evidence for differential regulation of multiple transcripts of the gonadotropin releasing hormone receptor in the ovine pituitary gland; effect of estrogen.

The number of pituitary gonadotropin-releasing hormone receptors (GnRH-R) varies across the estrous cycle. We report that there is variable expression of the differently-sized GnRH-R transcripts in cyclic ewes and in an experimental model. During the follicular phase of the cycle, and compared to the luteal phase, there was increased expression of the 1.5, 2.3 and 3.7 kilobase (kb) transcripts with no change in the levels of the 5.6 or the 1.2 kb transcripts. Steady state levels of mRNA for luteinising hormone beta and common alpha subunit were also increased in the follicular phase of the cycle. In hypothalamo-pituitary disconnected ovariectomised ewes given pulsatile GnRH replacement, injection of estrogen increased the 1.5, 2.3 and 3.7 kb, while the levels of the 5.6 and 1.2 kb transcripts were not altered. We conclude that the differential regulation of GnRH-R mRNA occurs through a direct effect of E on the pituitary.

Paradoxical effect of gonadotrophin-inhibiting hormone to negatively regulate neuropeptide Y neurones in mouse arcuate nucleus.

Regulation of reproduction and energy homeostasis are linked, although our understanding of the central neural mechanisms subserving this connection is incomplete. Gonadotrophin-inhibiting hormone (GnIH) is a neuropeptide that negatively regulates reproduction and stimulates food intake. Neuropeptide Y (NPY) and products of the pro-opiomelanocortin (POMC) precursor (ß-endorphin melanocortins) are appetite regulating peptides produced in the neurones of the arcuate nucleus; these peptides also regulate reproduction. In the present study, we determined the effects of GnIH on NPY and POMC neurones. Using brain slices from mice with transgenes for fluorescent tags in the two types of neurone and patch clamp electrophysiology, a predominant inhibitory effect of GnIH was observed. GnIH (100 nM) inhibited the firing rate in POMC cells, confirming the results of previous studies and consistent with the stimulatory effect of GnIH on food intake. Paradoxically (i.e. because both GnIH and NPY stimulate food intake), GnIH also had a predominantly inhibitory effect on action potential activity in NPY cells. GnIH also inhibited the secretion of NPY and α-melanocyte-stimulating hormone secretion in incubated hypothalamic blocks. GnIH (100 ng) injected into the cerebral ventricles of mice did not increase the number of NPY cells that were positively immunostained for c-Fos. Finally, dual label immunocytochemistry showed that 20% of NPY neurones had close contacts from GnIH fibres/varicosities. In conclusion, we confirm a negative effect of GnIH on POMC cells and demonstrate a paradoxical reduction of electrophysiological and functional activity in NPY cells.

Using intranasal lidocaine to reduce food intake.

OBJECTIVE: Develop a dose-response curve for the effect of intranasal lidocaine on food intake. DESIGN: Healthy obese subjects had food intake, ratings of hunger, desire to eat, craving and fullness measured at lunch after an overnight fast. Four treatments were given as nose drops (0.5-0.6 ml per nostril) 5 min before the meal in a double-blind manner with a four period crossover design including a 7-day washout between periods. The treatments were saline, 2.5, 10 and 25 mg lidocaine per nostril. The order of administration was randomly assigned to each subject. Electrocardiograms, vital signs, chemistry panels, complete blood counts (CBC) and nasal inspections were carried out before and after each dose. SUBJECTS: Forty-seven subjects were screened, 34 were randomized and 20 subjects completed all four study periods in the trial. The subjects were 39+/-12.5 (s.d) years of age, had a weight of 91+/-13.0 kg, a height of 167+/-10.3 cm, 56% were women, 47% were African-American and 53% were Caucasian. MEASUREMENTS: Food intake, rating of hunger, desire to eat, craving and fullness are measures of efficacy. Adverse events, electrocardiograms, vital signs, chemistry panels, nasal inspections, CBC and physical exams are measures of safety. RESULTS: The mean reduction in food intake vs saline control in the 20 subjects completing all four study periods was 3.3+/-7% (s.d), 4.2+/-8.5% and 7.4+/-7.3% in the 2.5 mg, 10 and 25 mg per nostril groups, respectively (P=NS). Hunger and desire to eat in subjects who completed at least one study period decreased dose dependently (P<0.03, at the 25 mg per nostril dose). There were no clinically significant changes in safety measures, electrocardiograms, vital signs, chemistry panels, CBC or nasal inspections. CONCLUSION: Intranasal lidocaine reduced hunger and the desire to eat, but this did not translate into a significant reduction in food intake suggesting that intranasal lidocaine will not have value in treating obesity.

Pancreatic polypeptide in obese children before and after weight loss.

OBJECTIVE: Little is known concerning pancreatic polypeptide (PP) in weight loss and in childhood obesity. METHODS: Fasting PP, leptin and insulin concentrations were determined in 38 obese children and compared with 35 lean children of the same age, gender and pubertal stage. Furthermore, changes of PP concentrations over a 1-year period were analyzed in the obese children participating in a weight loss intervention program. RESULTS: Obese children had significantly (P<0.01) lower PP, and higher leptin and insulin levels compared to lean children. In multiple linear regression analysis, PP was significantly negatively correlated to body mass index (P<0.01), but not to leptin, insulin, age, gender and pubertal stage. Changes of PP did not significantly correlate to changes of insulin (r=0.07, P=0.343) and leptin (r=-0.02, P=0.459). The substantial weight loss in 17 children led to a significant (P<0.05) increase in PP and decrease in insulin and leptin. In the 21 children without substantial weight loss, there were no significant changes in PP, insulin and leptin. CONCLUSIONS: PP concentrations are decreased in obese children and independent of age, gender, pubertal stage, leptin and insulin. The decrease of PP in obese children normalized after weight loss. Therefore, low PP concentrations reflect the overweight status, rather than cause it.

Estrogen transiently increases delayed rectifier, voltage-dependent potassium currents in ovine gonadotropes.

Treatment of gonadotropes with estrogen (E) changes the electrophysiological response to gonadotropin-releasing hormone (GnRH) such that the cells are hyperpolarised immediately after stimulation with GnRH and then generate action potentials more frequently than non-E-treated cells. We investigated the role of K+ current in this altered response to GnRH using cultures of ewe pituitary cells enriched for gonadotropes. K+ current density was measured using nystatin-perforated whole-cell recordings in the voltage clamp mode. Treatment of cells with E for 16-20 h significantly (p < 0.01) increased the unit K+ current to 180% of that in vehicle-treated cells. Outward current in these cells flows predominantly through voltage-dependent, delayed rectifier K+ channels (IK), and E alters the magnitude of this current. The effect of E to increase the K+ current was dose- and time-dependent and was maximal after 16-20 h. The unit K+ current values returned to pre-treatment levels after 36 h of E treatment. Several cells were studied both before and after E treatment and the average effect of E on these cells was to increase the unit K+ current by 90%. The time-course of the effect of E on K+ current density is the same as the effect of E to increase LH release in vitro and in vivo. We conclude that the increase in K+ current may be an important part of the mechanism whereby E acts on gonadotropes to facilitate the LH surge which triggers ovulation.

The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis.

Arcuate nucleus neurons are known to be responsive to a wide array of hormones and nutrients, including leptin, insulin, gonadal steroids and glucose. In addition to potential transport mechanisms, peripheral substances may access these neurons via arcuate cell bodies in and projections to the median eminence, a region considered to be a circumventricular organ. The arcuate is a potent site of leptin action, probably mediating a component of leptin's effects via arcuate neuropeptide Y/agouti-related peptide (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons, and implicating this structure in the long-term control of energy stores. However, ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, may also stimulate feeding and weight gain, in part through action on receptors in arcuate NPY neurons. Since ghrelin is secreted by the stomach upon content depletion, with a half-life of no more than an hour, the arcuate nucleus may also be important in sensing and responding to acute changes in nutrients. We have developed a system for recording from arcuate POMC neurons using a mouse containing a transgene in which the POMC promoter is driving expression of the green fluorescent protein (GFP). In these mice, 99% of the beta-endorphin positive neurons express GFP, making whole cell patch clamp recordings from the sparsely distributed POMC neurons facile. All of the POMC neurons appear to be activated by leptin, via two different mechanisms, while approximately 30-50% of the neurons appear to be inhibited by a gamma-melanocyte stimulating hormone (MSH) specific agonist. The latter result suggests that the melanocortin-3 receptor (MC3-R) may act as an autoinhibitory receptor on some POMC neurons. This hypothalamic slice preparation also confirms the responsiveness of arcuate POMC neurons to a wide variety of nutrients and hormones. Thus the arcuate melanocortin system is best described as a conduit of many diverse signals involved in energy homeostasis, with leptin acting tonically to regulate the responsiveness of the circuit to a wide variety of hormones and nutrients.

Hypothalamic circuitry of neuropeptide Y regulation of neuroendocrine function and food intake via the Y5 receptor subtype.

Neuropeptide Y (NPY) displays diverse modes of action in the CNS including the modulation of feeding behavior, gonadotropin releasing hormone release, and stress responses. Many of the above physiological actions have been at least partially attributed to actions of NPY on the NPY Y5 receptor subtype. We utilized an antibody directed against the NPY Y5 receptor to characterize the distribution of this receptor in the rat brain. Using Western blot analysis, this antibody recognized a single major band at approximately 57 kD. To further verify the specificity of the antibody, animals were treated for 5 days with antisense oligonucleotides for the Y5 receptor. The antisense treatment significantly reduced food intake and body weight. Furthermore, the Y5 antibody detected a significant decrease in Y5 receptor protein. Y5-like immunoreactivity (-ir) was observed throughout the hypothalamus, thalamus, hippocampus and cortex. Double-label immunofluorescence demonstrated that Y5-ir was colocalized with the following neuronal phenotypes in the hypothalamus, gonadotropin-releasing hormone, neurophysins, corticotropin-releasing hormone, and gamma-amino butyric acid. In addition, functional interactions were demonstrated by the presence of close appositions of NPY fibers with Y5-ir expressing cells. The wide distribution of the Y5 receptor-ir, as well as the colocalization within specific neuronal populations, agrees with the distribution of the Y5 receptor mRNA and the known physiological roles of the NPY/Y5 system. The role of the NPY/Y5 receptor system as a mediator between signals of peripheral energy availability and reproductive neuroendocrine function is discussed.

Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus.

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.