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Appetite Suppression and Weight Reduction by a Centrally Active Aminosterol Rexford S Appetite Suppression and Weight Reduction by a Centrally Active Aminosterol Rexford S. Ahima,1 Hiralben R. Patel,1 Nobuhiko Takahashi,1 Yong Qi,1 Stanley M. Hileman,2 and Michael A. Zasloff3 The rise in obesity and its complications has generated metabolite of cholesterol that was originally isolated from enormous interest in the regulation of feeding and body the dogfish shark (Squalus acanthias) liver during a weight. We show that a spermine metabolite of choles- search for naturally occurring antimicrobial compounds terol (MSI-1436) decreases body weight, specifically (4,5). MSI-1436 is structurally similar to squalamine (MSI- fat, by suppressing feeding and preventing the reduc- 1256) except for a spermine side-chain at C-3 on the tion in energy expenditure, hormonal changes, and pat- cholesterol A-ring (4,5). The bioactivity of MSI-1436 is also terns of neuropeptide expression normally associated dependent on a seven ␣-OH and sulfated moiety at C-25 with weight loss. MSI-1436 enters the brain after pe- (5). Unexpectedly, MSI-1436 was shown to inhibit feeding ripheral injection and is more potent when injected into and decrease body weight in a highly specific manner in the cerebral ventricle (intracerebroventricular [ICV]). Systemic or ICV MSI-1436 administration induced sim- normal and obese rodents (5). ilar patterns of Fos immunoreactivity in the brain, MSI-1436 is distributed to the brain and several periph- especially the paraventricular hypothalamic nucleus eral tissues (5). A single or intermittent treatment with (PVN). This brain region integrates neural signals from MSI-1436 results in a prolonged reduction in food intake hypothalamic and brain stem nuclei and regulates feed- and body weight and has been partly attributed to its long ing behavior, autonomic function, and neuroendocrine half-life (ϳ7 days in rodents) (5). However, it is unclear function. Microinjection of MSI-1436 into the PVN po- whether MSI-1436–induced weight loss is due to appetite tently suppressed feeding and reduced body weight for suppression alone. Moreover, although it had been sug- several days. Unlike caloric restriction, MSI-1436 gested that MSI-1436 is more potent when administered decreased mRNA levels of agouti-related peptide and into the cerebral ventricle, its targets in the central ner- neuropeptide Y in the hypothalamus. These findings indicate that MSI-1436 acts in the brain to regulate food vous system are unknown. The objective of this study was intake and energy expenditure, likely through suppres- to investigate the contributions of energy intake and sion of orexigenic hypothalamic pathways. Diabetes 51: expenditure to the sustained effect of MSI-1436 on body 2099–2104, 2002 weight and determine whether the biological activity of MSI-1436 in the brain is mediated by well-known hypotha- lamic neuronal pathways that mediate feeding behavior and energy balance. besity is highly prevalent in the U.S. and other developed countries and is increasing world- wide (1,2). This epidemic has serious public RESEARCH DESIGN AND METHODS health consequences because obesity is associ- Experiments were performed in accordance with guidelines and regulations O of the National Institutes of Health and Institutional Animal Care and Use ated with excess mortality and morbidity from type 2 Committee of the University of Pennsylvania. diabetes, cardiovascular disease, and other complications Determine the effect of MSI-1436 on food intake and energy expendi- (1,2). Diet and exercise remain the cornerstone of obesity ture. Male 12-week-old C57Bl/6J mice (Jackson Laboratories, Bar Harbor, management; however, it is likely that many patients will ME) were housed individually in a 12:12 h light-dark cycle (lights on at 0600; require drug treatment to reduce body weight and prevent temperature 22°C) and allowed normal laboratory diet and water ad libitum. complications (3). Here, we describe the anti-obesity Synthetic MSI-1436 and squalamine (MSI-1256) were provided by Genaera (Plymouth Meeting, PA). Our preliminary studies confirmed that squalamine action of a novel aminosterol. MSI-1436 is a spermine did not affect food intake or body weight (5). In contrast, intraperitoneal (IP) injection of MSI-1436 during the light or dark cycle reduced food intake and body weight in a dose-dependent manner (data not shown). We selected a 1 From the Division of Endocrinology, Diabetes and Metabolism, University of lower dose of MSI-1436 that did not suppress drinking as previously described Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the 2Depart- (5). MSI-1436 (5 mg/kg IP ϫ three doses) was administered at 0900–1000 at ment of Physiology and Pharmacology, Robert C. Byrd Health Sciences ϭ ϭ Center, West Virginia University, Morgantown, West Virginia; and the 3George- 3-day intervals to a group of mice (n 6). Control mice (n 6) were treated ␮ ϭ town University School of Medicine, Washington, DC. with vehicle (100 l endotoxin-free H2O IP). A third group of mice (n 6) was Address correspondence and reprint requests to Rexford S. Ahima, Univer- pair-fed to the daily intake of MSI-1436 mice. Indirect calorimetry was sity of Pennsylvania School of Medicine, Division of Endocrinology, Diabetes performed after the final treatment. The mice were acclimatized to the test and Metabolism, 764 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA cage for 2 days, and energy expenditure was measured at 15-min intervals for 19104. E-mail: [email protected]. 24 h on the third day (Oxymax Equalflow System; Columbus Instruments, Received for publication 13 February 2002 and accepted in revised form 3 Columbus, OH) (6). The following settings were used per cycle: air flow 500 April 2002. ml/min, sample flow 400 ml/min, settle time 120 s, measuring time 60 s, AGRP, agouti-related peptide; BAT, brown adipose tissue; CART, cocaine- ϭ and amphetamine-regulated transcript; MCR, melanocortin receptor; NEFA, temperature 22°C, respiratory exchange ratio (RER) volume of carbon nonesterified fatty acid; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; dioxide generated (VCO2) divided by oxygen consumption (VO2). Heat (kcal/ PVN, paraventricular hypothalamic nucleus; RER, respiratory exchange ratio; h) ϭ 3.815 ϩ 1.232 ϫ RER. Total and ambulatory activity were measured UCP, uncoupling protein. simultaneously with photodetectors (Optovarimex System; Columbus Instru- DIABETES, VOL. 51, JULY 2002 2099 CHOLESTEROL METABOLITE DECREASES WEIGHT ments). Rectal temperature was measured with a thermistor (Physitemp histologically, and only data from confirmed PVN injection (n ϭ 4/group) were Instruments, Clifton, NJ). included in the analysis. The mice were killed by CO2 inhalation, and blood was obtained by cardiac Analyze the effect of MSI-1436 on hypothalamic neuropeptide expres- puncture. Glucose and triglycerides (Sigma, St. Louis, MO) and nonesterified sion. Male 12-week-old C57Bl/6J mice were treated with three injections of ␮ fatty acids (NEFAs) (Wako Chemicals, Richmond, VA) were measured with MSI-1436 (5 mg/kg IP) or vehicle (100 l endotoxin-free H2O) at 3-day intervals. enzyme assays. Plasma insulin, leptin, corticosterone, and thyroxine were A third group was pair-fed to MSI-1436 treatment. Three days after the last measured by radioimmunoassay as previously described (7,8). Uncoupling injection, the mice were killed, hypothalami were dissected, and quantitative protein (UCP)-1 mRNA was measured in brown adipose tissue (BAT) by RT-PCR analysis was performed using specific primers for agouti-related peptide Northern blot analysis using a cDNA probe (provided by Mitch Lazar, (AGRP), neuropeptide Y (NPY), pro-opiomelanocortin (POMC), cocaine- and University of Pennsylvania). The rest of the carcass was dried to a constant amphetamine-regulated transcript (CART), melanin-concentrating hormone, and ␤ weight at 60°C to determine water content and digested in ethanol-KOH, and -actin (14). For corticotropin-releasing hormone, the following primers were Ј Ј Ј fat (triglyceride) content was measured with a colorimetric assay (Sigma) (8). used: upstream, 5 -gcatcctgagagaagtccctctg-3 ; downstream, 5 -aagttagccgcagcgt- Ј We determined whether MSI-1436 could prevent the hyperphagia normally ggtc-3 , corresponding to nucleotides 437–459 and 1476–1495 (15). The signal was associated with fasting. Male 12-week-old C57Bl/6J mice were fasted for 48 h measured by Phosphoimager (Molecular Dynamics, Sunnyvale, CA), and densi- and received a single injection of MSI-1436 (5 mg/kg IP) or vehicle (n ϭ ties corresponding to mRNA expression of various peptides were normalized to ␤ 6/group) after the fast. They were housed in individual cages and allowed ad -actin (14). Data analysis. The effects of MSI-1436 on food intake, body weight, and other libitum access to normal diet and water. Food intake and body weight were parameters were compared by ANOVA. Pairwise differences between groups measured daily. Feeding frequency and duration were monitored using were determined using Fisher’s protected least significant differences test; infrared detectors (Vitalview System; Mini Mitter, Bend, OR). The data on P Ͻ 0.05 was considered significant. feeding frequency and duration were collated in 1-h bins and analyzed using Actiview software (Mini Mitter). Determine the dose response to intracerebroventricular versus sys- RESULTS temic MSI-1436 treatment. Male Sprague-Dawley rats (250–300 g) were obtained from Taconic Farms (Germantown, NY), housed in a 12:12 h MSI-1436 decreases body weight by inhibiting food light-dark cycle (lights on at 0600; temperature 22°C), and allowed normal intake and increasing energy expenditure. To ascer- laboratory food and water ad libitum. The animals were anesthetized with tain whether weight reduction by MSI-1436 was mediated sodium pentobarbital, and a 22-gauge stainless steel guide cannula with entirely by inhibition of feeding, the daily intake of a group obturator (Plastics One, Roanoke, VA) was implanted unilaterally in the of pair-fed mice was matched with that of MSI-1436– lateral cerebral ventricle using the following coordinates: 0.8 mm posterior to bregma, 1.5 mm lateral to the midline, and 4 mm below the skull.
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