The neuroendocrinology of obesity
01 Sep 2001-Endocrinology and Metabolism Clinics of North America (Elsevier)-Vol. 30, Iss: 3, pp 765-785
TL;DR: As the nosology of obesity improves, diagnostic efficiency and therapeutic success should increase, leading to a decrease in associated morbidity, mortality, and socioeconomic ramifications.
About: This article is published in Endocrinology and Metabolism Clinics of North America.The article was published on 2001-09-01. It has received 59 citations till now. The article focuses on the topics: Birth weight & Weight loss.
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National Institutes of Health1, University of California, Irvine2, University of Louisville3, Sheba Medical Center4, Istituto Superiore di Sanità5, University of North Carolina at Chapel Hill6, Universidad Miguel Hernández de Elche7, University of Parma8, University of Turin9, University of Chicago10, University of Massachusetts Amherst11, University of Missouri12
TL;DR: This review will examine changes to the incidence of obesity, T2D and non-alcoholic fatty liver disease (NAFLD), the contribution of genetics to these disorders and describe the role of the endocrine system in these metabolic disorders.
599 citations
TL;DR: The data establish trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat‐specific weight loss and improve insulin and leptin levels.
Abstract: Trodusquemine (MSI-1436) causes rapid and reversible weight loss in genetic models of obesity. To better predict the potential effects of trodusquemine in the clinic, we investigated the effects of trodusquemine treatment in a murine model of diet-induced obesity (DIO). Trodusquemine suppressed appetite, reduced body weight (BW) in a fat-specific manner, and improved plasma insulin and leptin levels in mice. Screening assays revealed that trodusquemine selectively inhibited protein-tyrosine phosphatase 1B (PTP1B), a key enzyme regulating insulin and leptin signaling. Trodusquemine significantly enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) β and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and/or hypothalamic tissue in vivo. These data establish trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat-specific weight loss and improve insulin and leptin levels.
173 citations
TL;DR: The fat cell has been found to be an endocrine organ that produces several peptides that are bioactive and participate in the regulation of adipocyte function that contributes to the development of obesity.
161 citations
Cites background from "The neuroendocrinology of obesity"
...Hypothalamic obesity is more frequent in children; craniopharyngioma is the tumor that is most often associated with hypothalamic obesity in this group of patients [94–97]....
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TL;DR: The role of the hypothalamic-pituitary-adrenal axis in the control of food intake and the pathogenesis of obesity is reviewed and the interactions between other neurosystems and this hormonal axis are discussed.
Abstract: The aim of this paper is to review the present knowledge on the role of the hypothalamic-pituitary-adrenal axis in the control of food intake and the pathogenesis of obesity and to discuss, on the basis of available literature, the interactions between other neurosystems and this hormonal axis. Food intake is influenced by a system of physiologic signals and behavioral controls consisting of positive and negative sensory feedback mechanisms. It is regulated by a complex neuroendocrine system consisting of peripheral signals (cortisol, leptin) in constant interplay with central neurosystems such as the cocaine-amfetamine-regulated transcript system. In these neurosystems, corticotropin-releasing hormone, pro-opiomelanocortin, melanin-concentrating hormone and neuropeptide Y are actively involved. The corticotropin-releasing hormone system is widely distributed throughout the brain, but it is particularly abundant in the medial parvocellular division of the paraventricular nucleus. Within the brain...
111 citations
Cites background from "The neuroendocrinology of obesity"
...There are three primary neuroendocrine components that control the regulation of food intake (Lusting 2001): the afferent peripheric system that is stimulated in response to a meal; the central nervous...
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...The binding of a-MSH to the melanocortin receptor (MCR) 4 in the PVN induces anorexia while the intracerebroventricular (icv) administration of MCR4 antagonists stimulates feeding (Lusting 2001)....
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...Furthermore, leptin may potentiate the action of other short-term satiety signals (Lusting 2001)....
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TL;DR: It is indicated that Caucasian patients with the greater degree of insulin hypersecretion appeared to derive the most benefit from treatment, and the observed safety profile was consistent with the known effects of octreotide from previous studies.
Abstract: To compare changes in weight in obese patients who received long-acting octreotide (octreotide LAR) at one of three dose levels (20, 40, or 60 mg) or placebo over 6 months and to identify the lowest dose of octreotide LAR that safely achieved optimal weight loss. Randomized, double-blind, placebo-controlled trial of octreotide LAR at three dose levels. A total of 172 adults (28 men and 144 women) with at least moderate obesity (body mass index (BMI) range 30–65 kg/m2) and evidence of insulin hypersecretion were enrolled. Patients were predominantly either Caucasian (50.0%) or African American (45.3%). The mean age (38±11 year), weight (110.7±23 kg), and BMI (39.8±6.5 kg/m2) were similar across the four treatment groups. Efficacy measures included weight, BMI, fasting serum glucose; triglycerides; percentage of total body fat and abdominal fat as measured by dual-energy X-ray absorptiometry; skin fold thickness; waist-to-hip circumference; leptin; percentage of carbohydrates, fat, and protein ingested; nutritional evaluation (including dietary analysis – 3-day food record); quality of life (QoL; using the Impact of Weight on Quality of Life-Lite™); Beck Depression Inventory; and Carbohydrate Craving Questionnaire. Safety measures included medical history, vital signs, physical examinations, hematology, blood chemistries, thyroid function tests, hemoglobin A1c, gallbladder ultrasound, electrocardiograms, and adverse events. After 6 months of treatment, patients receiving 40 or 60 mg of octreotide LAR experienced statistically significant weight loss compared to baseline, with mean differences from placebo in percent weight change of −1.98 and −1.87%, respectively. This finding was accompanied by statistically significant mean decreases in BMI compared to baseline, that is, a mean decrease of 0.73 and 0.79 kg/m2 for the 40 and 60 mg treatment arms, respectively. The observed weight loss was progressive during the 6-month treatment in the two higher dose groups. The lowest dose to reach statistical significance in weight loss after 6 months' treatment was 40 mg. Post hoc analysis revealed a 3.5–3.8% weight loss at month 6 in the two higher dose groups among Caucasian patients having insulin secretion greater than the median of the cohort, defined as CIRgp (corrected insulin response at the glucose peak) ⩾1.43. There were no statistically significant changes in QoL scores, body fat, leptin concentration, Beck Depression Inventory, or macronutrient intake. Mean changes of blood glucose AUC0–180 min during an oral glucose tolerance test in patients taking octreotide LAR were 39–40 mg/dl h higher than those on placebo. A total of 7–21% of the patients taking octreotide LAR reached a 5% or greater decrease in body weight from Baseline, compared to 11% for the placebo group. This was not statistically significant. The most common adverse events included diarrhea, headache, cholelithiasis, nausea, and abdominal pain. Octreotide LAR given at 40 or 60 mg resulted in statistically significant weight loss. A post hoc analysis stratifying patients by race and CIRgp indicated that Caucasian patients with the greater degree of insulin hypersecretion appeared to derive the most benefit from treatment. The observed safety profile was consistent with the known effects of octreotide from previous studies.
101 citations
Cites background from "The neuroendocrinology of obesity"
...Received 5 February 2005; revised 25 May 2005; accepted 31 July 2005; published online 13 September 2005 Correspondence: Dr RH Lustig, Division of Pediatric Endocrinology, University of California San Francisco, Box 0434, S-679, 513 Parnassus Avenue, San Francisco, CA 94143-0434, USA. E-mail: rlustig@peds.ucsf.edu International Journal of Obesity (2006) 30, 331–341 & 2006 Nature Publishing Group All rights reserved 0307-0565/06 $30....
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References
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TL;DR: The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
Abstract: The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
12,394 citations
TL;DR: The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelIn, a peptide specifically releases GH both in vivo and in vitro.
Abstract: Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown. Recent cloning of GHS-R strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH). We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine 3 is essential for the activity. We designate the GH-releasing peptide 'ghrelin' (ghre is the Proto-Indo-European root of the word 'grow'). Human ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.
8,073 citations
TL;DR: A model is described that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
6,178 citations
TL;DR: The role of leptin in the control of body weight and its relevance to the pathogenesis of obesity are reviewed.
Abstract: The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution However, the presence of excess adipose tissue can be maladaptive A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system Leptin also signals nutritional status to several other physiological systems and modulates their function Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity
5,335 citations
TL;DR: It is proposed that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary, suggesting an involvement in regulation of energy balance.
Abstract: The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the principal site of ghrelin synthesis is the stomach and not the hypothalamus Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons and in the brainstem Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary
3,894 citations