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Recombinant Variant of Ciliary Neurotrophic Factor for Weight Loss in Obese Adults

Published on Jan 1, 2017
Mark P. Ettinger18
Estimated H-index: 18
,
Thomas W. Littlejohn4
Estimated H-index: 4
+ 8 AuthorsCatherine Vicary1
Estimated H-index: 1
Abstract
Context Obese individuals tend to resist the weight-regulating effects of exog- enously administered leptin. A genetically engineered recombinant human variant cili- ary neurotrophic factor (rhvCNTF) that signals through leptinlike pathways in the hy- pothalamus has been shown to bypass leptin resistance in animal models of obesity. Objective To identify a safe and well-tolerated dose of rhvCNTF that causes weight loss in obese adults. Design, Setting, and Patients Twelve-week, double-blind, randomized, parallel- group, dose-ranging, multicenter clinical trial conducted at 2 university obesity clinics and at 5 independent clinical research clinics from March 2000 to August 2001, and including 173 nondiabetic obese adults, 82.6% of whom were women, with a mean (SD) body mass index of 41.1 (4.1). Interventions Patients were randomly assigned to receive daily for 12 weeks sub- cutaneous injections of placebo (n=32) or 0.3 µg/kg (n=32), 1.0 µg/kg (n=38), or 2.0 µg/kg (n=33) of rhvCNTF. Another group received 1.0 µg/kg for 8 weeks and placebo for 4 weeks (n=38), but they were not included in the primary analysis. All participants received instructions for a reduced-calorie diet (World Health Organiza- tion formula minus 500 kcal/d). Main Outcome Measures Change in weight during the 12-week double-blind treat- ment period and proportion of patients who achieved a weight loss of at least 5%. Results Of the 173 randomized patients, 123 (71%) completed the double-blind dosing period. Mean (SEM) changes in kilograms from baseline body weights were 0.1 (0.6) for placebo and �1.5 (0.6) for the 0.3, �4.1 (0.6) for the 1.0, and -3.4 (0.7) for the 2.0 µg/kg of rhvCNTF dosage groups (P.001, test for trend). Two patients (8.7%) in the placebo and 2 (8.3%) in the 0.3-µg/kg, 8 (29.6%) in the 1.0-µg/kg, and 5 (26%) in the 2.0-µg/kg treatment groups achieved a weight loss of at least 5%. Recombinant human variant CNTF was generally well tolerated although adverse events occurred in 75% of patients receiving placebo and 78% to 93% of patients receiving rhvCNTF, in a dose-related fashion, with mild injection site reactions as the most fre- quently reported adverse event. Conclusions In this initial, dose-ranging, 12-week study, treatment with rhvCNTF resulted in more weight loss than placebo. These preliminary findings require confir- mation in large prospective clinical trials.
  • References (14)
  • Citations (1)
References14
Newest
Published on Sep 1, 2002in Diabetes7.20
Thomas A. Buchanan70
Estimated H-index: 70
,
Anny H. Xiang42
Estimated H-index: 42
+ 8 AuthorsHoward N. Hodis63
Estimated H-index: 63
Type 2 diabetes frequently results from progressive failure of pancreatic β-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic β-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestational diabetes were randomized to placebo ( n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashio...
Satya P. Kalra86
Estimated H-index: 86
In the avalanche of recent information on the brain's control of energy homeostasis and the pathophysiology of obesity, there are two outstanding insights. One is enhanced knowledge of the neuroanatomy and neurochemistry of various components of the appetite regulation and energy expenditure networks in the hypothalamus, and the other is characterization of the neurobiology of leptin in regulating these two hypothalamic networks (1, 2). Leptin, an adipocyte-derived hormone normally transported a...
Philip D. Lambert13
Estimated H-index: 13
,
Keith D. Anderson22
Estimated H-index: 22
+ 8 AuthorsGeorge D. Yancopoulos139
Estimated H-index: 139
Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts v...
Published on Nov 1, 2000in The Journal of Clinical Endocrinology and Metabolism5.61
Christos S. Mantzoros103
Estimated H-index: 103
(BIDMC: Beth Israel Deaconess Medical Center),
Jeffrey S. Flier120
Estimated H-index: 120
(BIDMC: Beth Israel Deaconess Medical Center)
Obesity is a prevalent condition that is reaching epidemic proportions in the United States. Sixty-three percent of men and 55% of women are overweight [body mass index (BMI) of 25 kg/m 2 or higher], whereas 22% of the United States adult population is obese (BMI of 30 kg/m 2 or higher) (1). More importantly, the prevalence of obesity has almost doubled in the past decade (1). The consequences of obesity are serious. Approximately 80% of obese adults have at least one and 40% have two or more co...
Published on Oct 27, 1999in JAMA51.27
Steven B. Heymsfield101
Estimated H-index: 101
(Mount Sinai St. Luke's and Mount Sinai Roosevelt),
Andrew S. Greenberg68
Estimated H-index: 68
(Tufts University)
+ 8 AuthorsPam Hunt2
Estimated H-index: 2
(Amgen)
ContextThe protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss.ObjectiveTo determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults.DesignA randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998.SettingFour university nutrition and obesity clinics and 2 contract c...
Published on Mar 1, 1999in Obesity Research
George A. Bray114
Estimated H-index: 114
(Pennington Biomedical Research Center),
George L. Blackburn69
Estimated H-index: 69
(BIDMC: Beth Israel Deaconess Medical Center)
+ 8 AuthorsMonte L. Scheinbaum1
Estimated H-index: 1
BRAY, GEORGE A., GEORGE L. BLACKBURN, JAMES M. FERGUSON, FRANK L. GREENWAY, ADESH K. JAIN, CARL M. MENDEL, JOSEPH MEN-DELS, DONNA H. RYAN, SHERWYN L. SCHWARTZ, MONTE L. SCHEINBAUM, AND TIMOTHY B. SEATON. Sibutramine produces dose-related weight loss. Obes Res. Objective Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This pa...
Published on Feb 1, 1998in Endocrinology3.80
Bin Xu19
Estimated H-index: 19
(UF: University of Florida),
Michael G. Dube32
Estimated H-index: 32
(UF: University of Florida)
+ 5 AuthorsDavid Martin42
Estimated H-index: 42
(Amgen)
Although ciliary neurotropic factor (CNTF) is a tropic factor in nervous system development and maintenance, peripheral administration of this cytokine also causes severe anorexia and weight loss. The neural mechanism(s) mediating the loss of appetite is not known. As hypothalamic neuropeptide Y (NPY) is a potent orexigenic signal, we tested the hypothesis that CNTF may adversely affect NPYergic signaling in the hypothalamus. Intraperitoneal administration of CNTF (250μ g/kg) daily for 4 days si...
Isabelle Gloaguen10
Estimated H-index: 10
(Schering-Plough),
Patrizia Costa8
Estimated H-index: 8
(Schering-Plough)
+ 10 AuthorsLex H.T. Van der Ploeg46
Estimated H-index: 46
(MSD: Merck & Co.)
Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNT...
Published on Jul 28, 1995in Science41.04
Mary Ann Pelleymounter20
Estimated H-index: 20
,
Mary Jane Cullen12
Estimated H-index: 12
+ 4 AuthorsF Collins1
Estimated H-index: 1
C57BL/6J mice with a mutation in the obese (ob) gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB protein lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. In addition, metabolic rate, body temperature, and activity levels were increased by this treatment. None of these parameters was altered beyond the level observed in lean controls,...
Published on Jul 28, 1995in Science41.04
L. A. Campfield9
Estimated H-index: 9
,
Françoise J. Smith21
Estimated H-index: 21
+ 2 AuthorsPaul Burn43
Estimated H-index: 43
The recent positional cloning of the mouse ob gene and its human homology has provided the basis to investigate the potential role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses of OB protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. ...
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