Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity

Air, Ellen L.; Strowski, Mathias Z.; Benoit, Stephen C.; Conarello, Stacey; Salituro, Gino; Guan, Xiao-Ming; Liu, Kun; Woods, Stephen C.; Zhang, Bei B.

doi:10.1038/nm0202-179

Cited by 160 publications

(86 citation statements)

References 21 publications

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“…4C). Although each test is limited in its ability to detect aversive effects from a wide variety of causes, collectively these data strongly suggest that the antibody does not make animals sick (2). Thus, the reduction in food intake occurring 10 h after IMC-A1 injection is unlikely to be a manifestation of illness caused by nonspecific toxicity of the antibody.…”

Section: Possible Adverse Effectsmentioning

confidence: 92%

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Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Sun¹,

Malabunga²,

Tonra³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Leibel RL, Kussie P. Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys. Am J Physiol Endocrinol Metab 292: E964 -E976, 2007. First published November 28, 2006; doi:10.1152/ajpendo.00089.2006.-We generated three fully human monoclonal antibody antagonists against fibroblast growth factor receptor-1 (FGFR1) that potently block FGF signaling. We found that antibodies targeting the c-splice form of the receptor (FGFR1c) were anorexigenic when administered intraperitoneally three times weekly to mice, resulting in rapid, dose-dependent weight loss that plateaued (for doses Ͼ4 mg/kg) at 35-40% in 2 wk. Animals appeared healthy during treatment and regained their normal body weights and growth trajectories upon clearance of the antibodies from the bloodstream. Measurements of food consumption and energy expenditure indicated that the rapid weight loss was induced primarily by decreased energy intake and not by increased energy expenditure or cachexia and was accompanied by a greater reduction in fat than lean body mass. Hypophagia was not caused through malaise or illness, as indicated by absence of conditioned taste aversion, pica behavior, and decreased need-induced salt intake in rats. In support of a hypothalamic site of action, we found that, after intraperitoneal injections, anti-FGFR1c (IMC-A1), but not a control antibody, accumulated in the median eminence and adjacent mediobasal hypothalamus and that FGFR1c is enriched in the hypothalamus of mice. Furthermore, a single intracerebroventricular administration of 3 g of IMC-A1 via the 3rd ventricle to mice caused an ϳ36% reduction in food intake and an ϳ6% weight loss within the ensuing 24 h. Our data suggest that FGF signaling through FGFR1c may play a physiological role in hypothalamic feeding circuit and that blocking it leads to hypophagia and weight loss. energy homeostasis; hypothalamus; fibroblast growth factor receptor; food intake; obesity THE FGF-FGFR AXIS (fibroblast growth factor-fibroblast growth factor receptor) plays a central role in embryonic development, osteogenesis, tissue maintenance, and repair (24,42,46). FGF signaling is complex: at least 22 ligands are known that signal through four distinct cell surface receptors (FGFR1, -2, -3, and -4). Some FGF-knockouts (such as FGF4, -8, -9, -10, -18 and FGFR1) are embryonic lethal; others generate relatively mild phenotypes due to considerable redundancy in the signaling pathway(s) (10,24,42,46). Loss-of-function mutations in FGFR1 have been implicated in instances of hypogonadotropic hypogonadism (Kallmann syndrome), indicating a role for the receptor in human central nervous system (CNS)/hypothalamic development (45). FGF ligand-receptor binding induces receptor dimerization and autophosphorylation, leading to downstream activation of effector molecules such as mitogen-activating protein kinase (MAPK). In FGFR1, -2, and -3, alternative splicing of the exons encoding the third IgG-like domain produces either the b-or...

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Section: Possible Adverse Effectsmentioning

confidence: 92%

“…The conditioned taste aversion (CTA) test has been used to test the involvement of general malaise or illness in drug-induced reduction of appetite (2,55). To get the rats used to drinking saccharin, 18-h water-deprived animals were given brief access to saccharin solution (0.01% in distilled water).…”

Section: Aversion Testsmentioning

confidence: 99%

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Sun¹,

Malabunga²,

Tonra³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Studies using monkeys and rats have revealed that intracerebroventricular (icv) insulin administration diminishes the amount of food intake and body weight [16][17][18]. This food intake-lowering effect of insulin is reported to be reversed by the icv administration of PI3K inhibitor [19].…”

Section: Central Insulin Action and Glucose/energy Metabolismmentioning

confidence: 99%

Central insulin-mediated regulation of hepatic glucose production [Review]

Inoue

2016

Endocr J

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Abstract. Insulin controls hepatic glucose production (HGP) and maintains glucose homeostasis through the direct action of hepatic insulin receptors, as well as the indirect action of insulin receptors in the central nervous system. Insulin acts on insulin receptors in the hypothalamic arcuate nucleus, activates ATP-sensitive potassium channels in a phosphoinositide 3-kinase (PI3K)-dependent manner, induces hyperpolarization of the hypothalamic neurons, and regulates HGP via the vagus nerve. In the liver, central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes. Activated STAT3 suppresses the gene expression of gluconeogenic enzymes, thereby reducing HGP. It has become evident that nutrients such as glucose, fatty acids, and amino acids act upon the hypothalamus together with insulin, affecting HGP. On the other hand, HGP control by central insulin action is impeded in obesity and impeded by insulin resistance due to disturbance of PI3K signaling and inflammation in the hypothalamus or inhibition of STAT3 signaling in the liver. Although the mechanism of control of hepatic gluconeogenic gene expression by central insulin action is conserved across species, its importance in human glucose metabolism has not been made entirely clear and its elucidation is anticipated in the future.Key words: Hypothalamus, Insulin, Liver, Vagus nerve, STAT3 THE LIVER plays a central role in the maintenance of whole-body glucose homeostasis, by adjusting glucose production according to the energy balance. The master regulator of hepatic glucose production (HGP) is insulin, as the liver is exposed to portal blood, which displays high insulin concentrations of approximately three times that in venous blood [1]. Indeed, in diabetes mellitus, the increase of HGP is closely related to the rise of fasting blood level [2]. HGP is strongly controlled by direct actions of insulin on hepatocytes [3]. When bound to its receptor, insulin suppresses HGP via the activation of phosphoinositide 3-kinase (PI3K) signal transduction pathway consisting of insulin receptor substrate (IRS), PI3K, phosphoinositide-dependent kinase 1 (PDK1) and Akt [4]. Thus, liver-specific insulin receptor knockout mice or impaired PI3K signal transduction exhibit hyperinsulinemia and glucose intolerance with impaired insulin-dependent suppression of HGP [5][6][7][8]. Meanwhile, insulin is known to control HGP not only by direct mechanisms via hepatic insulin receptors, but also by indirect mechanisms mediated by insulin actions on other organs (Fig.1). It has been reported that insulin still suppresses HGP partially even in mice with PI3K signal transduction inhibition in the liver [8,9]. Further, in an investigation of the changes in HGP after intravenous and intraportal insulin administration, it was shown that the differences in portal blood insulin level, that is, the direct insulin action on hepatocytes, do not necessarily correlate with the effect of insulin on HGP suppression [10].Indirect suppressio...

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“…The brain and cerebrospinal fluid contain insulin, but since the brain produces little or no insulin, it must come from the periphery, consistent with there being both high plasma and cerebrospinal fluid insulin in obese subjects (for review, see Woods & Seeley, 2001). Finally, a smallmolecular-weight insulin receptor agonist has been shown to reduce food intake and increase expenditure when given either centrally or peripherally, possibly because it penetrates the brain better than insulin (Air et al 2002).…”

Section: Tonic Indicators Of Fat Stores: Leptin and Insulinmentioning

confidence: 99%

Central regulation of energy balance: inputs, outputs and leptin resistance

Arch

2005

Proc. Nutr. Soc.

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The regulation of energy balance is complex and, in man, imprecise. Nevertheless, in many individuals intake and expenditure are balanced with <1% error with little or no conscious effect. Essential components of such a regulatory system are signals, leptin and insulin, that reflect the size of lipid stores. Leptin receptors signal via phosphatidylinositol 3-kinase (as do insulin receptors) and via the transcription factor signal transducer and activator of transcription-3 to activate various types of neurone. Obese rodents, and possibly man, are resistant to leptin; in some cases because of genetic or perinatal programming (primary resistance), but commonly in response to high leptin levels (secondary resistance). Secondary leptin resistance may be a result of reduced transport of leptin to the brain or down-regulation of leptin signalling. Signals that reflect lipid stores form the tonic homeostatic regulatory system. They interact with episodic homeostatic signals carried by neurones, hormones and metabolites to regulate meal size and frequency. They also interact with signals related to the palatability of food, biorhythms and learning. Many neurotransmitters and hormones mediate responses to more than one input (e.g. gastric and adipocyte leptin), but are nevertheless most involved with particular inputs (e.g. leptin with adipocyte fat stores). Feeding can be divided into appetitive (preparation for feeding) and consummatory phases, which can both be further subdivided. Different sets of neurotransmitters and hormones are involved at each stage. In the long term it may be possible to customise obesity therapies according to those inputs and outputs that are most disturbed and most amenable to intervention in individual subjects.

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Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity

Cited by 160 publications

References 21 publications

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Central insulin-mediated regulation of hepatic glucose production [Review]

Central regulation of energy balance: inputs, outputs and leptin resistance

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