Intranasal delivery of mouse [D‐Leu‐4]‐OB3, a synthetic peptide amide with leptin‐like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin‐resistant C57BLK/6‐m <i>db/db</i> mice

Waldrop, Megan A.; Leinung, Matthew C.; Lee, D. W.; Grasso, Patricia

doi:10.1111/j.1463-1326.2010.01243.x

Cited by 18 publications

(7 citation statements)

References 29 publications

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“…The exciting studies related to the therapeutic potential of intranasal insulin in the treatment of AD have been described above. Additionally, studies demonstrating the metabolic effects of intranasal leptin administration may also have therapeutic potential in the treatment cognitive decline observed in obesity, type 2 diabetes and AD (Schulz et al, 2004; Waldrop et al, 2010). …”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Food for thought: The role of appetitive peptides in age-related cognitive decline

Fadel

Jolivalt

Reagan

2013

Ageing Research Reviews

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Through their well described actions in the hypothalamus, appetitive peptides such as insulin, orexin and leptin are recognized as important regulators of food intake, body weight and body composition. Beyond these metabolic activities, these peptides also are critically involved in a wide variety of activities ranging from modulation of immune and neuroendocrine function to addictive behaviors and reproduction. The neurological activities of insulin, orexin and leptin also include facilitation of hippocampal synaptic plasticity and enhancement of cognitive performance. While patients with metabolic disorders such as obesity and diabetes have greater risk of developing cognitive deficits, dementia and Alzheimer’s disease (AD), the underlying mechanisms that are responsible for, or contribute to, age-related cognitive decline are poorly understood. In view of the importance of these peptides in metabolic disorders, it is not surprising that there is a greater focus on their potential role in cognitive deficits associated with aging. The goal of this review is to describe the evidence from clinical and pre-clinical studies implicating insulin, orexin and leptin in the etiology and progression of age-related cognitive decline. Collectively, these studies support the hypothesis that leptin and insulin resistance, concepts normally associated with the hypothalamus, are also applicable to the hippocampus.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Food for thought: The role of appetitive peptides in age-related cognitive decline

Fadel

Jolivalt

Reagan

2013

Ageing Research Reviews

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“…Similar to CCK, there is evidence to suggest that the entire leptin molecule is not required for stimulating its biological actions [11,12]. Thus, a synthetic peptide corresponding to amino acid residues 116-122 of mouse leptin, with an additional substitution of the Leu residue at position 4 with its D-isomer, namely [D-Leu-4]-OB3, retains all significant biological actions of full length leptin [12,13]. Leptin mediates energy balance by acting through two distinct receptors encoded by the Ob-R gene (also known as LEPR), a short-form Ob-Ra and a long-form Ob-Rb receptor [13].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, a synthetic peptide corresponding to amino acid residues 116-122 of mouse leptin, with an additional substitution of the Leu residue at position 4 with its D-isomer, namely [D-Leu-4]-OB3, retains all significant biological actions of full length leptin [12,13]. Leptin mediates energy balance by acting through two distinct receptors encoded by the Ob-R gene (also known as LEPR), a short-form Ob-Ra and a long-form Ob-Rb receptor [13]. In addition, there are a number of other isoforms of the leptin receptor that may have physiological significance [14].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

2013

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Aims/hypothesis Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively. Methods The actions and overall therapeutic use of (pGluGln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice. Results (pGlu-Gln)-CCK-8 had prominent (p<0.01 to p< 0.001), acute feeding-suppressive effects, which were significantly augmented (p<0.05 to p<0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p<0.05 to p<0.001), energy intake (p<0.01), circulating triacylglycerol (p<0.01), nonfasting glucose (p<0.05 to p<0.001) and triacylglycerol deposition in liver and adipose tissue (p<0.001). All treatment regimens improved glucose tolerance (p<0.05 to p<0.001) and insulin sensitivity (p<0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p<0.001) energy expenditure. Conclusions/interpretationThese studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.

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“…Defective transport into the CNS has been identified as the cause of leptin resistance in the majority of cases of human obesity [1][2][3]. [D-Leu-4]-OB3 has been shown to be biologically active in genetically obese diabetic ob/ob and db/db mouse models, and in non-obese streptozotocin-induced insulin-deficient Swiss Webster mice [7,10,19,20,23,25]. It is worthy of special note that demonstration of the anti-obesity and anti-hyperglycemic effects of [D-Leu-4]-OB3 in leptin-resistant db/db mice indicates a mechanism of action that involves recruitment of signaling pathways that achieve leptin-like effects independent of activation of the long isoform of the leptin receptor.…”

Section: Discussionmentioning

confidence: 99%

Myristic acid conjugation of [D-Leu-4]-OB3, a biologically active leptin-related synthetic peptide amide, significantly improves its pharmacokinetic profile and efficacy

2014

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Intranasal delivery of mouse [D‐Leu‐4]‐OB3, a synthetic peptide amide with leptin‐like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin‐resistant C57BLK/6‐m db/db mice

Cited by 18 publications

References 29 publications

Food for thought: The role of appetitive peptides in age-related cognitive decline

Food for thought: The role of appetitive peptides in age-related cognitive decline

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

Myristic acid conjugation of [D-Leu-4]-OB3, a biologically active leptin-related synthetic peptide amide, significantly improves its pharmacokinetic profile and efficacy

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