Is the GLP-1 system a viable therapeutic target for weight reduction?

Tong, Jenny; Sandoval, Darleen A.

doi:10.1007/s11154-011-9170-8

Cited by 19 publications

(27 citation statements)

References 90 publications

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“…This is of interest as in patients with type 2 diabetes, an association between increased nausea and weight loss has been suggested (48). Our observation, however, is consistent with studies from animal models that show that GLP-1-dependent actions on food intake and visceral illness can be dissociated (40,49) and are confined to distinct brain areas (40).…”

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

“…As GLP-1 receptors are expressed in the brain as well as in peripheral tissues, weight loss might be caused by a combination of central and peripheral GLP-1 actions (37,38,40,50). In the brain, GLP-1 acts to increase energy expenditure and to reduce food intake according to animal studies (38,40). With respect to the inhibition of food intake, this involves GLP-1 receptor activation in the paraventricular nucleus of the hypothalamus, the hindbrain and in the nuclei of the mesolimbic reward system (37,38,40,51).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, treatment with GLP-1 analogues promotes significant weight loss in diabetic as well as non-diabetic obese subjects (33,34,35,36). GLP-1 receptors are expressed in the stomach, duodenum and exocrine pancreas as well as in several hypothalamic and brainstem nuclei involved in appetite regulation (37,38,39,40). Although the precise mechanisms that mediate the effects of GLP-1 analogues on weight reduction are yet to be unravelled, there may be a combination of effects on the gastrointestinal tract as well as on the brain (37,38,40).…”

Section: Introductionmentioning

confidence: 99%

“…GLP-1 receptors are expressed in the stomach, duodenum and exocrine pancreas as well as in several hypothalamic and brainstem nuclei involved in appetite regulation (37,38,39,40). Although the precise mechanisms that mediate the effects of GLP-1 analogues on weight reduction are yet to be unravelled, there may be a combination of effects on the gastrointestinal tract as well as on the brain (37,38,40). It is unknown whether GLP-1 analogues can lead to weight loss in patients with obesity caused by hypothalamic damage, and whether these compounds could be an option for their treatment.…”

Section: Introductionmentioning

confidence: 99%

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GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases

Zoicas

Droste

Mayr

et al. 2013

European Journal of Endocrinology

100

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Background: Patients with hypothalamic pathology often develop morbid obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic patients and cause weight loss in obese patients by yet unknown mechanisms. Here we tested whether GLP-1 analogues were also effective in the treatment of obesity and associated metabolic alterations in patients with hypothalamic disease. Methods: Nine patients (eight with type 2 diabetes mellitus) with moderate to severe hypothalamic obesity were treated with GLP-1 analogues for up to 51 months. Body weight, homeostasis model assessment -insulin resistance (HOMA-IR), HbA1c and lipids were assessed. Results: Eight patients experienced substantial weight loss (K13.1G5.1 kg (range K9 to K22)). Insulin resistance (HOMA-IR K3.2G3.5 (range K9.1 to 0.8)) and HbA1c values (K1.3G1.4% (range K4.5 to 0.0)) improved under treatment (24.3G18.9 months (range 6 to 51)). Five patients reported increased satiation in response to the treatment. Two of the eight patients complained about nausea and vomiting and one of them abandoned therapy because of sustained gastrointestinal discomfort after 6 months. One patient suffered from intolerable nausea and vomiting and discontinued treatment within 2 weeks. Conclusion: GLP-1 analogues can cause substantial and sustained weight loss in obese patients with hypothalamic disease. This offers a new approach for medical treatment of moderate to severe hypothalamic obesity and associated metabolic alterations.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases

Zoicas

Droste

Mayr

et al. 2013

European Journal of Endocrinology

100

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Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice

et al. 2015

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Aims/hypothesis We assessed the contribution of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) signalling to thermogenesis induced by high-fat diet (HFD) consumption. Furthermore, we determined whether brown adipose tissue (BAT) activity contributes to weight loss induced by chronic subcutaneous treatment with the GLP-1R agonist, liraglutide, in a model of diet-induced obesity. Methods Metabolic phenotyping was performed using indirect calorimetry in wild-type (WT) and Glp1r-knockout (KO) mice during chow and HFD feeding at room temperature and at thermoneutrality. In a separate study, we investigated the contribution of BAT thermogenic capacity to the weight lowering effect induced by GLP-1 mimetics by administering liraglutide (10 or 30 nmol kg−1 day−1 s.c.) to diet-induced obese (DIO) mice for 6 or 4 weeks, respectively. In both studies, animals were subjected to a noradrenaline (norepinephrine)-stimulated oxygen consumption (V̇O2) test. Results At thermoneutrality, HFD-fed Glp1r-KO mice had similar energy expenditure (EE) compared with HFD-fed WT controls. However, HFD-fed Glp1r-KO mice exhibited relatively less EE when housed at a cooler standard room temperature, and had relatively lower V̇O2 in response to a noradrenaline challenge, which is consistent with impaired BAT thermogenic capacity. In contrast to the loss of function model, chronic peripheral liraglutide treatment did not increase BAT activity as determined by noradrenaline-stimulated V̇O2 and BAT gene expression. Conclusions/interpretation These data suggest that although endogenous GLP-1R signalling contributes to increased BAT thermogenesis, this mechanism does not play a significant role in the food intake-independent body weight lowering effect of the GLP-1 mimetic liraglutide in DIO mice.

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Crosstalk between diabetes and brain: Glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration

Duarte

Candeias

Correia

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

122

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According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.

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Is the GLP-1 system a viable therapeutic target for weight reduction?

Cited by 19 publications

References 90 publications

GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases

GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases

Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice

Crosstalk between diabetes and brain: Glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration

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