Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain ...transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.
Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue ...resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.
Neuropeptide Y Deficiency Attenuates Responses to Fasting and High-Fat Diet in Obesity-Prone Mice
Hiralben R. Patel 1 ,
Yong Qi 1 ,
Evan J. Hawkins 1 ,
Stanley M. Hileman 2 ,
Joel K. Elmquist 3 ,
...Yumi Imai 1 and
Rexford S. Ahima 1
1 Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
2 Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia
3 Department of Medicine, Center for Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, Texas
Address correspondence and reprint requests to Rexford S. Ahima, MD, PhD, University of Pennsylvania School of Medicine, Division
of Endocrinology, Diabetes and Metabolism, 764 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104. E-mail:
ahima{at}mail.med.upenn.edu
Abstract
Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic
action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed
a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted
during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than
wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice
have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of
an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are
refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and
increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and
increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity
in both wild-type and NPYko mice.
AGRP, agouti-related peptide
BAT, brown adipose tissue
CART, cocaine-and amphetamine-regulated transcript
CRH, corticotropin-releasing hormone
DIO, diet-induced obesity
MCH, melanin-concentrating hormone
NPY, neuropeptide Y
POMC, proopiomelanocortin
PVN, paraventricular nucleus
UCP, uncoupling protein
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 27, 2006.
Received May 16, 2005.
DIABETES
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. Zasloff 3
...1 Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
2 Department of Physiology and Pharmacology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West
Virginia
3 Georgetown University School of Medicine, Washington, DC
Abstract
The rise in obesity and its complications has generated enormous interest in the regulation of feeding and body weight. We
show that a spermine metabolite of cholesterol (MSI-1436) decreases body weight, specifically fat, by suppressing feeding
and preventing the reduction in energy expenditure, hormonal changes, and patterns of neuropeptide expression normally associated
with weight loss. MSI-1436 enters the brain after peripheral injection and is more potent when injected into the cerebral
ventricle (intracerebroventricular ICV). Systemic or ICV MSI-1436 administration induced similar patterns of Fos immunoreactivity
in the brain, especially the paraventricular hypothalamic nucleus (PVN). This brain region integrates neural signals from
hypothalamic and brain stem nuclei and regulates feeding behavior, autonomic function, and neuroendocrine function. Microinjection
of MSI-1436 into the PVN potently suppressed feeding and reduced body weight for several days. Unlike caloric restriction,
MSI-1436 decreased mRNA levels of agouti-related peptide and neuropeptide Y in the hypothalamus. These findings indicate that
MSI-1436 acts in the brain to regulate food intake and energy expenditure, likely through suppression of orexigenic hypothalamic
pathways.
Footnotes
Address correspondence and reprint requests to Rexford S. Ahima, University of Pennsylvania School of Medicine, Division of
Endocrinology, Diabetes and Metabolism, 764 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104. E-mail: ahima{at}mail.med.upenn.edu .
Received for publication 13 February 2002 and accepted in revised form 3 April 2002.
AGRP, agouti-related peptide; BAT, brown adipose tissue; CART, cocaine- and amphetamine-regulated transcript; MCR, melanocortin
receptor; NEFA, nonesterified fatty acid; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PVN, paraventricular hypothalamic
nucleus; RER, respiratory exchange ratio; UCP, uncoupling protein.
DIABETES
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