Prophylactic Application of MA-[d-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Prevents or Slows the Progression of Obesity, Insulin Resistance, and Cognitive Impairment in a Mouse Model of Type 2 Diabetes Mellitus

Chua, Fu Yee; Novakovic, Zachary M.; Grasso, Patricia

doi:10.1007/s10989-021-10248-2

Cited by 2 publications

(3 citation statements)

References 26 publications

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“…A recently-published follow-up study indicated that the mechanism of action by which MA-[D-Leu-4]-OB3 improves cognitive function in these mouse models appears to be related to its ability to enhance insulin sensitivity peripherally and in the brain, and to reduce TNF-α-induced neurodegeneration (Hirschstein et al, 2020). Most recently, the prophylactic capacity of MA-[D-Leu-4]-OB3 to prevent or slow the progression of obesity, insulin resistance, and cognitive impairment in a mouse model of T2DM has been reported (Chua et al, 2021). The ability of MA-[D-Leu-4]-OB3 to improve serum lipid profiles in mouse models of T1DM and T2DM (Hirschstein et al, 2021), suggests an additional application targeted toward reducing the risk of adverse cardiovascular events in humans that are associated with both T1DM and T2DM.…”

Section: Assessing the Effects Of Leptin Mimetics On Cognitive Functionmentioning

confidence: 97%

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

Grasso

2022

Front. Aging Neurosci.

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In this review, the current understanding of leptin’s role in energy balance, glycemic regulation, and cognitive function is examined, and its involvement in maintaining the homeostatic “harmony” of these physiologies is explored. The effects of exercise on circulating leptin levels are summarized, and the results of clinical application of leptin to metabolic disease and neurologic dysfunction are reviewed. Finally, pre-clinical evidence is presented which suggests that synthetic peptide leptin mimetics may be useful in resolving not only the leptin resistance associated with common obesity and other elements of metabolic syndrome, but also the peripheral insulin resistance characterizing type 2 diabetes mellitus, and the central insulin resistance associated with certain neurologic deficits in humans.

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Section: Assessing the Effects Of Leptin Mimetics On Cognitive Functionmentioning

confidence: 97%

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

Grasso

2022

Front. Aging Neurosci.

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“…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. 21 In the 2 studies reported here, we provide evidence that oral delivery of MA-[D-Leu-4]-OB3, previously shown to modulate energy balance, glycemic control, serum lipids, and cognitive function in mouse models of leptin deficiency and leptin resistance, does not induce anorexia, severe weight loss, hypoglycemia, cognitive dysfunction, or any physical or behavioral clinical indicators of toxicity when given to male or female C57BL/6 mice at concentrations significantly higher than the minimal effective dose, or for extended periods of time.…”

Section: Introductionmentioning

confidence: 99%

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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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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Prophylactic Application of MA-[d-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Prevents or Slows the Progression of Obesity, Insulin Resistance, and Cognitive Impairment in a Mouse Model of Type 2 Diabetes Mellitus

Cited by 2 publications

References 26 publications

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

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

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