The melanocortin-4 receptor (MC4-R) is a G protein-coupled, seven-transmembrane receptor expressed in the brain. Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome, which results from ectopic expression of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R.

OB protein (also known as leptin), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks that regulate ingestive behavior and energy balance. OB protein provides a communication link from fat tissue and the brain. Rapidly accumulating evidence suggests that OB protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. The field has rapidly moved from cloning of the ob gene to demonstration of complex regulation of ob gene expression in adipose tissue in rats and humans, and then the demonstration of potent biological activity of OB protein in ob/ob, diet-induced, and lean mice as well as obese and lean rats but not in db/db obese mice. A significant milestone was our demonstration that central administration of OB protein lead to reductions in food intake, body weight and alterations in metabolism consistent with activation of the autonomic nervous system. These findings were followed by the identification of a central binding site for labelled OB protein in the choroid plexus in ob/ob, db/db and lean mice as well as lean and obese Zucker rats. The expression cloning of a central receptor, OB-R, from the mouse choroid plexus soon followed. The OB-R receptor was found to be expressed in the choroid plexus, the hypothalamus as well as several peripheral tissues. OB-R exists in multiple forms; the two major forms are a short form (with a truncated intracellular domain) and long form (with the complete intracellular domain). The long form is thought to be the form that signals and mediates the biological effects of OB protein. Initial in situ hybridization studies have demonstrated the mRNA for the long form OB-R receptor to be localized to the hypothalamus as well as peripheral sites. Recently, it was demonstrated that the db gene encodes the OB-R receptor. Evidence has been provided for a specific transport system for OB protein to cross the blood-brain-barrier and enter the brain of mice, rats and humans. The rate of transport can be decreased by high plasma concentrations of OB protein. Thus, reduced entry of OB protein to the brain may be one of the mechanisms of reduced sensitivity of the OB protein pathway in obese individuals. OB protein appears to also play a role in the important neuroendocrine adaptive responses to fasting and in the control of reproduction. Therapeutic approaches to the treatment of obesity based on OB protein ranging from OB protein by injection to OB-R receptor agonists and to upregulation of OB signalling pathways are under intense investigation.

Background Although preterm birth less than 37 weeks gestation is the leading cause of neonatal morbidity and mortality in the United States, the majority of data regarding preterm neonatal outcomes come from older studies, and many reports have been limited to only very preterm neonates. Delineation of neonatal outcomes by delivery gestational age is needed to further clarify the continuum of mortality and morbidity frequencies among preterm neonates. Objective We sought to describe the contemporary frequencies of neonatal death, neonatal morbidities, and neonatal length of stay across the spectrum of preterm gestational ages. Study Design Secondary analysis of an obstetric cohort of 115,502 women and their neonates who were born in 25 hospitals nationwide, 2008–2011. All live born non-anomalous singleton preterm (23.0–36.9 weeks of gestation) neonates were included in this analysis. The frequency of neonatal death, major neonatal morbidity (intraventricular hemorrhage grade III/IV, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II/III, bronchopulmonary dysplasia, persistent pulmonary hypertension), and minor neonatal morbidity (hypotension requiring treatment, intraventricular hemorrhage grade 1/2, necrotizing enterocolitis stage 1, respiratory distress syndrome, hyperbilirubinemia requiring treatment) were calculated by delivery gestational age; each neonate was classified once by the worst outcome they met criteria for. Results 8,334 deliveries met inclusion criteria. There were 119 neonatal deaths (1.4%). 657 (7.9%) neonates had major morbidity, 3,136 (37.6%) had minor morbidity, and 4,422 (53.1%) survived without any of the studied morbidities. Deaths declined rapidly with each advancing week of gestation. This decline in death was accompanied by an increase in major neonatal morbidity, which peaked at 54.8% at 25 weeks of gestation. As frequencies of death, and major neonatal morbidity fell, minor neonatal morbidity increased, peaking at 81.7% at 31 weeks of gestation. The frequency of all morbidities fell beyond 32 weeks. Neonatal length of hospital stay decreased significantly with each additional completed week of pregnancy; among babies delivered from 26 to 32 weeks of gestation, each additional week in utero reduced the subsequent length of neonatal hospitalization by a minimum of 8 days. The median post-menstrual age at discharge nadired at 35.7 weeks post-menstrual age for babies born at 32–33 weeks of gestation. Conclusions Our data show that there is a continuum of outcomes, with each additional week for gestation conferring survival benefit while reducing the length of initial hospitalization. These contemporary data can be useful for patient counseling regarding preterm outcomes.

The protein encoded by the obese (ob) gene, leptin, is secreted from adipose tissue and is proposed to act in the brain as an important regulator of food intake and body weight. To investigate the direct effects of leptin within the CNS, we injected 3.5 microg of either mouse or human leptin into the third ventricle (ICV) of lean Long-Evans rats or obese (fa/fa) Zucker rats, in which obesity results from a mutation in the leptin receptor gene. ICV administration of leptin reduced 4-h food intake in both deprived and non-deprived lean rats. In addition, repeated ICV administration produced a long-lasting reduction in body weight while peripheral administration of the same dose had no effect. ICV administration of the same dose of leptin into the third ventricle of obese Zucker rats did not reduce food intake. These results are consistent with the hypothesis that leptin has direct actions in the CNS as an afferent signal related to the state of energy stores in adipose tissue. Furthermore, insensitivity to these central effects of leptin may be an important determinant of obesity.

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Melanson, Kathleen J., Margriet S. WesterterpPlantenga, Wim H. M. Saris, Franç oise J. Smith, and L. Arthur Campfield. Blood glucose patterns and appetite in time-blinded humans: carbohydrate versus fat. Am. J. Physiol. 277 (Regulatory Integrative Comp. Physiol. 46): R337-R345, 1999.-We assessed the extent to which a possible synchronization between transient blood glucose declines and spontaneous meal initiation would lend support to the interpretation of a preload study with isoenergetic (1 MJ) isovolumetric high-fat or simple carbohydrate (CHO) preload drinks. Ten men (18-30 yr) fasted overnight and then were time blinded and made aware that they could request meals anytime. At first meal requests, volunteers consumed a preload; ad libitum meals were offered at subsequent requests. Postabsorptively, transient declines in blood glucose were associated with meal requests ( 2 ϭ 8.29). Subsequent meal requests occurred during ''dynamic declines'' in blood glucose after the peak induced by drink consumption (100%). These meal requests took twice as long to occur after high-fat than after CHO preloads (fat ϭ 126 Ϯ 21, CHO ϭ 65 Ϯ 15 min), consistent with differences in interpolated 65-min satiety scores (fat ϭ 38 Ϯ 8.2, CHO ϭ 16 Ϯ 4). Postprandially, transient blood glucose declines were associated with meal requests ( 2 ϭ 4.30). Spontaneous meal initiations were synchronized with transient and dynamic blood glucose declines. Synchronization of intermeal interval and dynamic declines related to higher satiating efficiency from high-fat preloads than from simple CHO preloads. glucostatic theory; food intake regulation; intermeal interval; satiety; hunger AN UNDERSTANDING OF FOOD intake regulation in humans is of profound clinical importance, particularly in approaching the prevention and treatment of obesity and eating disorders. Physiological, psychological, emotional, social, and cultural factors interact in a very complex manner to determine an individual's food intake. These various factors have been studied extensively over the past several decades,

A new framework for understanding the control of feeding behavior, with special emphasis on the evolution of hunger, the initiation of feeding, and its dependence on patterns of blood glucose, is the subject of this review. A perspective on the current status and future directions of this search for a more complete understanding of the regulation of feeding behavior in laboratory rats and humans is presented including theoretical and experimental components. First, a historical perspective on the role of blood glucose in the control of feeding is presented. Next, the theoretical approaches that have been applied to the control of feeding and had a strong influence on experimental feeding research are summarized. This is followed by a statement and overview of a current theory that has emerged from studies of the role of transient declines in blood glucose in the control of meal initiation. The current working hypothesis that transient declines in blood glucose are endogenous metabolic patterns that are detected and recognized by the central nervous system and are mapped into meal initiation in rats and are correlated with meal requests in humans are then presented. Then, the experimental studies on meal initiation and its dependence on patterns of blood glucose, first in rats and then in humans, are reviewed in detail. Finally, the future directions of the work, limitations, and the implications for the understanding of the control of feeding behavior and the regulation of energy balance are discussed.

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