Preparation of Leptin Antagonists by Site‐Directed Mutagenesis of Human, Ovine, Rat, and Mouse Leptin's Site III

Solomon, Gili; Niv-Spector, Leonora; Gonen-Berger, Dana; Callebaut, Isabelle; Djiane, Jean; Gertler, Arieh

doi:10.1196/annals.1378.094

Cited by 18 publications

(14 citation statements)

References 20 publications

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“…Our hypothesis was that leptin might be a cytokine involved in the maturation of the whole organism during the neonatal period. The recent availability of competitive leptin antagonists 16 has opened new opportunities to clarify the physiological role of leptin during specific periods of life. We previously demonstrated that the specific blockage of leptin action between postnatal days 2 and 13 resulted in a longterm alteration of food intake regulation and a higher susceptibility to diet-induced obesity.…”

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confidence: 99%

Postnatal leptin is necessary for maturation of numerous organs in newborn rats

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Postnatal leptin is necessary for maturation of numerous organs in newborn rats

et al. 2011

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“…To achieve this, we used a polyethylene glycol (PEG)ylated mouse leptin antagonist (PEG-MLA) (mutant L39A/D40A/F41A) that binds, but does not activate, the leptin receptor (38) to disrupt endogenous leptin signaling in adult wild-type mice. Peripheral administration of PEG-MLA competes with endogenous leptin binding in the periphery and blocks transport of leptin across the blood brain barrier (39).…”

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Acute Disruption of Leptin Signaling in Vivo Leads to Increased Insulin Levels and Insulin Resistance

et al. 2011

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Leptin, an adipocyte-derived hormone, plays an essential role in the maintenance of normal body weight and energy expenditure, as well as glucose homeostasis. Indeed, leptin-deficient ob/ob mice are obese with profound hyperinsulinemia, insulin resistance, and often hyperglycemia. Interestingly, low doses of exogenous leptin can reverse the hyperinsulinemia and hyperglycemia in these animals without altering body weight. The hyperinsulinemia in ob/ob mice may result directly from the absence of leptin signaling in pancreatic β-cells and, in turn, contribute to both obesity and insulin resistance. Here, we acutely attenuated endogenous leptin signaling in normal mice with a polyethylene glycol (PEG)ylated mouse leptin antagonist (PEG-MLA) to determine the contribution of leptin signaling in the regulation of glucose homeostasis. PEG-MLA was either injected or continuously administered via osmotic minipumps for several days, and various metabolic parameters were assessed. PEG-MLA-treated mice had increased fasting and glucose-stimulated plasma insulin levels, decreased whole-body insulin sensitivity, elevated hepatic glucose production, and impaired insulin-mediated suppression of hepatic glucose production. Moreover, PEG-MLA treatment resulted in increased food intake and increased respiratory quotient without significantly altering energy expenditure or body composition as assessed by the lean:lipid ratio. Our findings indicate that alterations in insulin sensitivity occur before changes in the lean:lipid ratio and energy expenditure during the acute disruption of endogenous leptin signaling.

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“…The objective of the studies described here was to test whether forebrain and hindbrain leptin receptors have different effects on body composition. This was accomplished by chronically infusing low doses of leptin into either the 3rd or the 4th ventricle of rats or by infusing the rats peripherally with leptin while inhibiting activation of forebrain or hindbrain receptors by infusion of the leptin receptor antagonist leptin mutein protein (mutein) (42) into the 3rd or 4th ventricle.…”

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Leptin-induced increase in body fat content of rats

Harris

2013

American Journal of Physiology-Endocrinology and Metabolism

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Harris RB. Leptin-induced increase in body fat content of rats. Am J Physiol Endocrinol Metab 304: E267-E281, 2013. First published December 4, 2012; doi:10.1152/ajpendo.00251.2012.-We previously reported that peripheral leptin infusions in chronically decrebrate rats, in which the forebrain is neurally isolated from the hindbrain, increased body fat and decreased energy expenditure. Any central leptin response in decerebrate rats would depend upon the hindbrain. Here, we tested whether selective activation of hindbrain leptin receptors increased body fat. Fourth ventricle infusion of 0.6 g leptin/day for 12 days increased body fat by 13% with no increase in food intake. Third ventricle leptin infusions decreased food intake, body fat, and lean tissue with a maximal response at 0.3 g leptin/day. To test whether hindbrain receptors opposed activity of hypothalamic receptors, rats received peripheral infusions of 40 g leptin/day and increasing 4th ventricle doses of the leptin receptor antagonist mutein protein. Mutein (3.0 g/day) reduced body fat in PBS-infused rats to the same level as leptin-infused rats and reduced lean tissue in all rats. Leptin, but not mutein, inhibited food intake. By contrast, 3.0 g/day mutein in the 3rd ventricle increased food intake and body fat in both PBS-and leptin-infused rats. In basal conditions, hindbrain leptin receptors may antagonize activity of forebrain receptors to protect lean and fat tissue, but there is no evidence for an anabolic role for hindbrain receptors when leptin is elevated. In a dietary study, rats increased energy intake when offered lard and 30% sucrose solution in addition to chow. Peripheral leptin infusion exaggerated the gain in body fat without altering energy intake confirming the potential for leptin to increase adiposity.forebrain; hindbrain; mutein leptin; body composition LEPTIN IS AN ADIPOSE-DERIVED HORMONE that is hypothesized to be a negative feedback signal in the regulation of energy balance (46). Central (12, 43) or peripheral (37) administration of leptin inhibits food intake of normal-weight rodents and corrects many aspects of the obesity syndrome in leptin-deficient ob/ob mice (20, 33). The negative energy balance associated with peripheral leptin treatment results in a specific loss of body fat mass and maintenance of lean body mass (20); by contrast, central administration of leptin may result in the loss of both fat and lean tissue (5). Even though leptin is an effective regulator of energy balance in normal-weight rodents, obese or aged animals have high circulating concentrations of endogenous leptin but are leptin resistant because leptin administration does not influence food intake or body weight (7,9,44,45).Early observations that peripheral leptin resistance preceded the development of central leptin resistance in high-fat-fed mice (9) led to the conclusion that peripheral leptin resistance results from a failure of leptin to cross the blood-brain barrier (1), whereas central leptin resistance is a failure of leptin to activate ...

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Preparation of Leptin Antagonists by Site‐Directed Mutagenesis of Human, Ovine, Rat, and Mouse Leptin's Site III

Cited by 18 publications

References 20 publications

Postnatal leptin is necessary for maturation of numerous organs in newborn rats

Postnatal leptin is necessary for maturation of numerous organs in newborn rats

Acute Disruption of Leptin Signaling in Vivo Leads to Increased Insulin Levels and Insulin Resistance

Leptin-induced increase in body fat content of rats

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