Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary‐induced obesity and insulin resistance

Porter, David W.; Kerr, Barry D.; Flatt, Peter R.; Hölscher, Christian; Gault, Victor

doi:10.1111/j.1463-1326.2010.01259.x

Cited by 133 publications

(90 citation statements)

References 41 publications

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“…Animal studies show similar changes. In a high-fat mouse model of T2DM, learning and memory and synaptic plasticity in the brain were impaired (Porter et al 2010b). In a high-fat-diet rat model of early-stage T2DM, insulin resistance was observed while dopamine release was attenuated and dopamine clearance was diminished in the basal ganglia, indicating that dopaminergic signalling is compromised in T2DM (Morris et al 2011).…”

Section: Insulin Desensitisation Can Occur In the Brainmentioning

confidence: 98%

Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases

Hölscher¹

2013

Journal of Endocrinology

236

161

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The incretin hormone glucagon-like peptide 1 (GLP-1) has many effects in the body. It is best known for the 'incretin effect', facilitating insulin release from the pancreas under hyperglycaemic conditions. Building on this, GLP-1 mimetics have been developed as a treatment for type 2 diabetes. In the course of monitoring of patients, it has become apparent that GLP-1 mimetics have a range of other physiological effects in the body. In preclinical trials, a substantial body of evidence has been built that these mimetics have neuroprotective and anti-inflammatory effects. GLP-1 also has very similar growth-factorlike properties to insulin, which is presumably the underlying basis of the neuroprotective effects. In preclinical studies of Alzheimer's disease (AD), Parkinson's disease (PD), stroke and other neurodegenerative disorders, it has been shown that most GLP-1 mimetics cross the blood-brain barrier and show impressive neuroprotective effects in numerous studies. In animal models of AD, GLP-1 mimetics such as exendin-4, liraglutide and lixisenatide have shown protective effects in the CNS by reducing b-amyloid plaques, preventing loss of synapses and memory impairments, and reducing oxidative stress and the chronic inflammatory response in the brain. In animal models of PD, exendin-4 showed protection of dopaminergic neurons in the substantia nigra and prevention of dopamine loss in the basal ganglia while preserving motor control. These encouraging findings have spawned several clinical trials, some of which have shown encouraging initial results. Therefore, GLP-1 mimetics show great promise as a novel treatment for neurodegenerative conditions.

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Section: Insulin Desensitisation Can Occur In the Brainmentioning

confidence: 98%

Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases

Hölscher¹

2013

Journal of Endocrinology

236

161

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“…Additionally, rats with the lowest hippocampal BDNF, who also had lower levels of CREB and the vesicle-associated synapsin I (114), had the lowest learning capacity (278). A HFD also has a negative impact on hippocampal LTP and plasticity (210), and some studies suggest that this impairment is related to BDNF. A diet high in saturated fat and refined sugars significantly reduced hippocampal BDNF compared with rats fed standard chow, which was accompanied by impaired LTP and poor performance on the Morris water maze, a spatial learning task (177).…”

Section: Bdnf and Neuronal Plasticitymentioning

confidence: 99%

The lighter side of BDNF

Noble

Billington

Kotz³

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

236

168

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Brain-derived neurotrophic factor (BDNF) mediates energy metabolism and feeding behavior. As a neurotrophin, BDNF promotes neuronal differentiation, survival during early development, adult neurogenesis, and neural plasticity; thus, there is the potential that BDNF could modify circuits important to eating behavior and energy expenditure. The possibility that "faulty" circuits could be remodeled by BDNF is an exciting concept for new therapies for obesity and eating disorders. In the hypothalamus, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are extensively expressed in areas associated with feeding and metabolism. Hypothalamic BDNF and TrkB appear to inhibit food intake and increase energy expenditure, leading to negative energy balance. In the hippocampus, the involvement of BDNF in neural plasticity and neurogenesis is important to learning and memory, but less is known about how BDNF participates in energy homeostasis. We review current research about BDNF in specific brain locations related to energy balance, environmental, and behavioral influences on BDNF expression and the possibility that BDNF may influence energy homeostasis via its role in neurogenesis and neural plasticity. food intake; body weight; ventromedial hypothalamus; paraventricular nucleus; brain-derived neurotrophic factor BRAIN-DERIVED NEUROTROPHIC factor (BDNF) is a member of the neurotrophin family of growth factors (151), along with nerve growth factor (152), and neurotrophin (NT) 3 (67, 163), NT 4/5 (28), and NT 6 (88). Neurotrophins are synthesized as 32-35-kDa pro-isoforms, which are later cleaved to mature forms that dimerize after translation and then act as receptor ligands (136). Whereas the precursor forms of other neurotrophins are constitutively secreted, the 32-kDa pro-BDNF is packaged into vesicles of a regulated pathway and is secreted in an activitydependent manner (87). Pro-BDNF may be secreted as is (48), cleaved by the extracellular protease plasmin (202), or interact with the pan-neurotrophin receptor p75 NTR and other receptors that cause an independent biological effect (244). Alternatively, pro-BDNF is processed to the mature form intracellularly by furin or proconvertases, where it forms C-terminal dimers (212, 226).Mature BDNF is considered the biologically active form, which has a high affinity for the tropomyosin-related kinase B (TrkB) receptor (130). Both BDNF and TrkB are present in presynaptic axon terminals and postsynaptic dendritic compartments of neurons, and they are capable of bidirectional release and activity [for review, see Tyler et al. (259)]. Typical of the neurotrophic factors, BDNF stimulates the development and differentiation of new neurons (3, 131) and promotes long-term potentiation (LTP) (139,140,205), and neuron survival (97,105,116). BDNF is abundantly expressed throughout the developing and mature CNS and in many peripheral tissues, including muscle, liver, and adipose (42,159,182,261). Regional differences between BDNF mRNA levels and protein concentrations in the CNS a...

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“…A similar effect with a reduction in food intake and body weight for the GLP1 receptor agonists liraglutide and exendin-4 has also been established in DIO rats fed the 60% HF diet from Research Diet [68] . Also, in DIO mice fed a diet containing 45% calories from fat, liraglutide reduces energy intake and body fat [69] . Thus, diet-induced obese rodents can be considered a valid animal model that reflects the effects seen in humans during pharmacological treatment that affects appetite and thereby reduces body weight.…”

Section: Polygenic Modelsmentioning

confidence: 99%

Laboratory animals as surrogate models of human obesity

Nilsson¹,

Raun²,

Yan³

et al. 2012

Acta Pharmacol Sin

240

104

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Obesity and obesity-related metabolic diseases represent a growing socioeconomic problem throughout the world. Great emphasis has been put on establishing treatments for this condition, including pharmacological intervention. However, there are many obstacles and pitfalls in the development process from pre-clinical research to the pharmacy counter, and there is no certainty that what has been observed pre-clinically will translate into an improvement in human health. Hence, it is important to test potential new drugs in a valid translational model early in their development. In the current mini-review, a number of monogenetic and polygenic models of obesity will be discussed in view of their translational character.Keywords: obesity; animal models; sibutramine; liraglutide; KK-A y mice; ob/ob mice; Zucker rat; diet-induced obesity models Acta Pharmacologica Sinica (2012) 33: 173-181; doi: 10.1038/aps.2011 Review IntroductionAs the prevalence of obesity is rising along with its socioeconomic consequences, the quest to find new treatments or a cure is also increasing (http://www.who.int/mediacentre/ factsheets/fs311/en/). Pharmaceutical treatment is one avenue that has been pursued, but currently there are only a limited number of compounds on the market because many have failed or been withdrawn because of side effects. Given that the development process from initial idea to marketed product typically requires more than 10 years and the attrition rate is notably high, it is important that the models used, whether in vitro or in vivo, are good surrogates for human obesity. Depending on the target in question, there are a number of models that can be applied. In the following pages, we will review the most widely used animal models in obesity research. We have categorized the different models into groups; rodent models are divided into monogenetic, polygenetic, and selectively bred diet-induced obesity (DIO) models, and finally we discuss the DIO pig model. To demonstrate the translational potential of the selected models, we have chosen two different model compound families that have been tested in human cohorts -sibutramine and liraglutide or other glucagon-like peptide-1 (GLP)-1 analogues [1 , 2] . Sibutramine is a serotonin and norepinephrine re-uptake inhibitor that was developed for the treatment of obesity and has been on the market for the past 9 years, although in most markets it has been withdrawn because of undesirable side effects [3] . Liraglutide is a GLP-1 analogue currently in phase 3 clinical development for severe obesity after demonstrating positive results in phase 2 trials [2] . By choosing the best suited animal model for a particular study, it is possible to make a qualified assessment as to whether target X and/or compound Y will have an impact in clinical practice at a much earlier point. Monogenic modelsKK-A y mice The inbred mouse strain KK was established in Japan and is a mouse model with peripheral insulin sensitivity and glucose intolerance [4] . Insulin resistance in the KK mouse i...

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Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary‐induced obesity and insulin resistance

Abstract: Liraglutide administered peripherally not only improves metabolic parameters but exerts additional beneficial effects on cognitive function and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established.

Cited by 133 publications

References 41 publications

Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases

Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases

The lighter side of BDNF

Laboratory animals as surrogate models of human obesity

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