[D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice

Wang, Anke; Anderson, Brian; Novakovic, Zachary M.; Grasso, Patricia

doi:10.1016/j.peptides.2017.12.012

Cited by 13 publications

(3 citation statements)

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“…14 Similar results were seen in diet-induced obese (DIO) mice, a model of type 2 diabetes mellitus (T2DM) and vascular dementia (VaD). 15 In both of these models, MA-[D-Leu-4]-OB3 not only reduced body weight gain and restored glycemic control, but also improved episodic memory. The prophylactic potential of MA-[D-Leu-4]-OB3 was also recently confirmed by its ability to prevent and/or slow the progression of obesity, insulin resistance, and cognitive impairment in normal C57BL/6 mice placed on a high-fat diet immediately after weaning.…”

Section: Introductionmentioning

confidence: 94%

“…12 This peptide has been modified over the years to improve its efficacy, pharmacokinetics, and method of delivery in a number of mouse models of human disease. [13][14][15][16][17][18][19][20] Most worthy of special note is the proven ability of these leptin mimetics to cross the BBB and to localize in the hypothalamus in all mouse models tested, 17 thus overcoming the central resistance associated with common obesity.…”

Section: Introductionmentioning

confidence: 99%

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Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

2023

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Although the regulatory influence of leptin on energy balance, glycemic control, immunity, reproduction, and cognition is well established, its clinical application to common obesity and its co-morbidities has been limited by impaired transport across the blood-brain barrier, and tendencies to induce adverse side effects. To circumvent these drawbacks, MA-[D-Leu-4]-OB3, a leptin-related synthetic peptide that mimics the metabolic and neurotrophic effects of leptin in mouse models of genetic and non-genetic obesity, diabetes, and cognitive dysfunction, has been developed. This report presents the results of our initial efforts to assess the safety of orally delivered MA-[D-Leu-4]-OB3. Two pre-clinical studies were done in male and female C57BL/6 mice: a short-term study with a high dose of MA-[D-Leu-4]-OB3 (50 mg/kg/100 μL/day) and a dose-response study with 3 increasing concentrations of MA-[D-Leu-4]-OB3 (16.6, 50, and 150 mg/kg/100 μL/day). Body weight, food and water intake, glucose tolerance, and episodic memory were evaluated. Once-daily cage-side clinical observations were conducted to detect any physical or behavioral indicators of toxicity. Our results indicate that all metabolic and neurologic endpoints tested were either unaffected or improved by MA-[D-Leu-4]-OB3, and no clinical indicators of toxicity were evident. Together with our previously reported efficacy data, these results provide additional evidence supporting further development of this novel synthetic peptide leptin mimetic as a first-in-class peptide drug candidate for the treatment of a number of metabolic and/or cognitive dysfunctions in humans.

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

2023

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“…Our laboratory has recently shown that MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, crosses the blood-brain barrier (Anderson et al, 2017), reduces body weight gain (Wang et al, 2018), improves insulin sensitivity (Wang et al, 2018;Anderson et al, 2019;Hirschstein et al, 2019), and normalizes episodic memory in mouse models of T1DM (Anderson et al, 2019) and T2DM (Hirschstein et al, 2019). In the present study, we hypothesized that the observed ability of MA-[D-Leu-4]-OB3 to improve cognitive function may be influenced not only by its effects on glycemic control, but also by actions associated with reducing serum concentrations of pro-inflammatory cytokines known to be associated with neuronal degeneration.…”

Section: Introductionmentioning

confidence: 99%

MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus

Hirschstein

Vanga

Wang

et al. 2020

Biochimica et Biophysica Acta (BBA) - General Subjects

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Leptin and the Blood‐Brain Barrier: Curiosities and Controversies

Banks

2021

Comprehensive Physiology

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Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play.

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[D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice

Cited by 13 publications

References 28 publications

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus

Leptin and the Blood‐Brain Barrier: Curiosities and Controversies

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