Leptin‐based glycopeptide induces weight loss and simultaneously restores fertility in animal models

Kovalszky, Ilona; Surmacz, Eva; Scolaro, Laura; Cassone, Marco; Ferla, Rita; Sztodola, Andras; Oláh, J.; Hatfield, Marcus P. D.; Lovas, Sándor; Ötvös, László

doi:10.1111/j.1463-1326.2009.01170.x

Cited by 28 publications

(16 citation statements)

References 52 publications

(62 reference statements)

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“…Following multiple daily intraperitoneal (i.p.) (0.5 mg/kg/day for 11 days) or intranasal (0.1 mg/kg/day for 10 days) injections, this leptin peptide controlled body weight gain in DIO mice [27]. The transport rate at the BBB is a key factor underlying the ability of any substance to enter the brain and efforts have been made to improve leptin transporter activity at the BBB.…”

Section: Introductionmentioning

confidence: 99%

Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity

Xiang

Yuan

Farr

et al. 2014

Journal of Controlled Release

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Modification of hydrophilic proteins with amphiphilic block copolymers capable of crossing cell membranes is a new strategy to improve protein delivery to the brain. Leptin, a candidate for the treatment of epidemic obesity, has failed in part because of impairment in its transport across the blood–brain barrier (BBB) that develops with obesity. We posit that modification of leptin with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly (ethylene oxide), Pluronic P85 (P85) might permit this protein to penetrate the BBB independently of its transporter, thereby overcoming peripheral leptin resistance. Here we report that peripherally administered leptin–P85 conjugates exhibit biological activity by reducing food intake in mouse models of obesity (ob/ob, and diet-induced obese mouse). We further generated two new leptin–P85 conjugates: one, Lep(ss)–P85(L), containing one P85 chain and another, Lep(ss)–P85(H), containing multiple P85 chains. We report data on their purification, analytical characterization, peripheral and brain pharmacokinetics (PK). Lep(ss)–P85(L) crosses the BBB using the leptin transporter, and exhibits improved peripheral PK along with increased accumulation in the brain compared to unmodified leptin. Lep(ss)–P85(H) also has improved peripheral PK but in a striking difference to the first conjugate penetrates the BBB independently of the leptin transporter via a non-saturable mechanism. The results demonstrate that leptin analogs can be developed through chemical modification of the native leptin with P85 to overcome leptin resistance at the level of the BBB, thus improving the potential for the treatment of obesity.

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Section: Introductionmentioning

confidence: 99%

Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity

Xiang

Yuan

Farr

et al. 2014

Journal of Controlled Release

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“…Among men, intentional weight loss (either by behavioral or surgical means) has been associated with a proportional increase in plasma levels of testosterone and gonadotropins as well as a decrease in levels of estradiol (47). The beneficial effects of weight loss on several 14.24 Rueda-Clausen · Ogunleye · Sharma Changes may still occur before final publication online and in print endocrine parameters associated with subfertility such as leptin, interleukin-6, and plasminogen activator inhibitor-1 have been extensively described, and in animal models, weight loss has been shown to improve obesity-induced subfertility (111). Similarly, bariatric surgery is associated with increased serum testosterone levels but paradoxically results in deterioration in sperm quality (185).…”

Section: Effect Of Sustained Weight Loss On Fertility/pregnancymentioning

confidence: 99%

Health Benefits of Long-Term Weight-Loss Maintenance

2015

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Obesity is a chronic and complex medical condition associated with a large number of complications affecting most organs and systems through multiple pathways. Strategies for weight management include behavioral, pharmacological, and surgical interventions, all of which can result in a reduction in obesity-related comorbidities and improvements in quality of life. However, subsequent weight regain often reduces the durability of these improvements. The objective of this article is to review evidence supporting the long-term effects of intentional weight loss on morbidity, mortality, quality of life, and health-care cost. Overall, considerable evidence suggests that intentional weight loss is associated with clinically relevant benefits for the majority of obesity-related comorbidities. However, the degree of weight loss that must be achieved and sustained to reap these benefits varies widely between comorbidities.

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“…Pegylated leptin, although with a longer half-life, does not cross the BBB [172], therefore it does not modify body weight in humans [173]. Other modifications showed to improve BBB transport and influence energy balance, such as the conjugation with a carbohydrate moiety [174], or the modification with trans-activating transcriptional activator or with PluronicR [171,175]. Further investigation about ERK-dependent release of leptin in the CSF has highlighted another possible approach attempting in the restoration of ERK signaling when leptin resistance is mainly due to a diminished leptin transport in the brain.…”

Section: Improvement Of Leptin Transport Through the Bbbmentioning

confidence: 99%