Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models

2018 ◽  
Vol 10 (472) ◽  
pp. eaat3392 ◽  
Author(s):  
Elizabeth A. Killion ◽  
Jinghong Wang ◽  
Junming Yie ◽  
Stone D.-H. Shi ◽  
Darren Bates ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Body Weight Gain ◽  
Association Studies ◽  
Conditional Knockout ◽  
Genome Wide Association Studies ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.

scholarly journals Current and emerging concepts on the role of peripheral signals in the control of food intake and development of obesity

2012 ◽  
Vol 108 (5) ◽  
pp. 778-793 ◽  
Author(s):  
F. A. Duca ◽  
M. Covasa
Keyword(s):  
Body Weight ◽  
Energy Homeostasis ◽  
Peptide Yy ◽  
Body Weight Gain ◽  
Gut Peptides ◽  
Gastrointestinal Peptides ◽  
Term Energy ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity

The gastrointestinal peptides are classically known as short-term signals, primarily inducing satiation and/or satiety. However, accumulating evidence has broadened this view, and their role in long-term energy homeostasis and the development of obesity has been increasingly recognised. In the present review, the recent research involving the role of satiation signals, especially ghrelin, cholecystokinin, glucagon-like peptide 1 and peptide YY, in the development and treatment of obesity will be discussed. Their activity, interactions and release profile vary constantly with changes in dietary and energy influences, intestinal luminal environment, body weight and metabolic status. Manipulation of gut peptides and nutrient sensors in the oral and postoral compartments through diet and/or changes in gut microflora or using multi-hormone ‘cocktail’ therapy are among promising approaches aimed at reducing excess food consumption and body-weight gain.

scholarly journals Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies For The Treatment Of Obesity, Do Agonists = Antagonists?

2019 ◽  
Author(s):  
Elizabeth A Killion ◽  
Shu-Chen Lu ◽  
Madeline Fort ◽  
Yuichiro Yamada ◽  
Murielle M Véniant ◽  
...  
Keyword(s):  
Weight Gain ◽  
Association Studies ◽  
Mouse Genetics ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Studies ◽  
Genome Wide ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity

Abstract Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is associated with obesity in human genome-wide association studies (GWAS). Similarly, mouse genetic studies indicate that loss of function alleles and GIP overexpression both protect from high-fat diet (HFD)-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when co-dosed or molecularly combined with glucagon-like peptide-1 (GLP-1) analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the two approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.

scholarly journals Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies for the Treatment of Obesity, Do Agonists = Antagonists?

2019 ◽  
Vol 41 (1) ◽  
pp. 1-21 ◽  
Author(s):  
Elizabeth A Killion ◽  
Shu-Chen Lu ◽  
Madeline Fort ◽  
Yuichiro Yamada ◽  
Murielle M Véniant ◽  
...  
Keyword(s):  
Weight Gain ◽  
Association Studies ◽  
Mouse Genetics ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Studies ◽  
Genome Wide ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity

Abstract Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mouse genetic studies indicate that loss of function alleles and glucose-dependent insulinotropic polypeptide overexpression both protect from high-fat diet–induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when codosed or molecularly combined with glucagon-like peptide-1 analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the 2 approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity, and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.

scholarly journals Effect of Body Weight on Age at Onset in Huntington Disease

2021 ◽  
Vol 7 (4) ◽  
pp. e603
Author(s):  
Jorien M.M. van der Burg ◽  
Patrick Weydt ◽  
Georg Bernhard Landwehrmeyer ◽  
N. Ahmad Aziz
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Huntington Disease ◽  
Association Studies ◽  
Age At Onset ◽  
Disease Onset ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Clinical Progression ◽  
Genetically Determined

ObjectiveWeight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD.MethodsUsing data from different recent genome-wide association studies, we performed a 2-sample mendelian randomization (MR) analysis to assess whether genetic markers of body mass index (BMI) are causally related to residual age at onset in HD, i.e., the difference between observed and expected age at onset based on mutation size. Our study had a statistical power of 90% to detect a causal effect of ≥3.8 months per BMI unit change at a type I error rate of 0.05.ResultsInverse-variance weighted MR estimates showed that a higher genetically determined BMI was not causally related to residual age at onset in HD (β = −0.44 years per unit increase in BMI, confidence interval: −1.33 to 0.46, p = 0.34). All other complementary (nonparametric) MR regression methods yielded similar results.ConclusionsAlthough maintaining a healthy and stable body weight remains important in patients with HD, promoting weight gain with the aim of delaying disease onset or slowing down disease progression should be discouraged. Our findings point toward the existence of underlying pathologic processes that dictate both the rate of clinical progression and weight loss in HD, which need further elucidation as targeting these pathways, rather than body weight per se, could be of therapeutic value.

scholarly journals GPR40 reduces food intake and body weight through GLP-1

2017 ◽  
Vol 313 (1) ◽  
pp. E37-E47 ◽  
Author(s):  
Judith N. Gorski ◽  
Michele J. Pachanski ◽  
Joel Mane ◽  
Christopher W. Plummer ◽  
Sarah Souza ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Partial Agonist ◽  
Glucose Lowering ◽  
Partial Agonists ◽  
Lower Glucose ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
G Protein Coupled

G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.

scholarly journals Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

2020 ◽  
Author(s):  
Melissa Conti Mazza ◽  
Victoria Nguyen ◽  
Alexandra Beilina ◽  
Jinhui Ding ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Association Studies ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Genome Wide Association Studies ◽  
Double Knockout ◽  
Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

scholarly journals Specificity and Redundancy of Profilin 1 and 2 Function in Brain Development and Neuronal Structure

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2310
Author(s):  
Marina Di Domenico ◽  
Melanie Jokwitz ◽  
Walter Witke ◽  
Pietro Pilo Boyl
Keyword(s):  
Actin Polymerization ◽  
Conditional Knockout ◽  
Brain Morphology ◽  
Actin Dynamics ◽  
Neuronal Structure ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Neuronal Stem Cell ◽  
Neuronal Precursors ◽  
Redundant Functions

Profilin functions have been discussed in numerous cellular processes, including actin polymerization. One puzzling aspect is the concomitant expression of more than one profilin isoform in most tissues. In neuronal precursors and in neurons, profilin 1 and profilin 2 are co-expressed, but their specific and redundant functions in brain morphogenesis are still unclear. Using a conditional knockout mouse model to inactivate both profilins in the developing CNS, we found that threshold levels of profilin are necessary for the maintenance of the neuronal stem-cell compartment and the generation of the differentiated neurons, irrespective of the specific isoform. During embryonic development, profilin 1 is more abundant than profilin 2; consequently, modulation of profilin 1 levels resulted in a more severe phenotype than depletion of profilin 2. Interestingly, the relevance of the isoforms was reversed in the postnatal brain. Morphology of mature neurons showed a stronger dependence on profilin 2, since this is the predominant isoform in neurons. Our data highlight redundant functions of profilins in neuronal precursor expansion and differentiation, as well as in the maintenance of pyramidal neuron dendritic arborization. The specific profilin isoform is less relevant; however, a threshold profilin level is essential. We propose that the common activity of profilin 1 and profilin 2 in actin dynamics is responsible for the observed compensatory effects.

scholarly journals Association of GWAS-Based Candidate Genes with HDL-Cholesterol Levels before and after Bariatric Surgery in the Swedish Obese Subjects Study

2011 ◽  
Vol 96 (6) ◽  
pp. E953-E957 ◽  
Author(s):  
Mark A. Sarzynski ◽  
Peter Jacobson ◽  
Tuomo Rankinen ◽  
Björn Carlsson ◽  
Lars Sjöström ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Weight Loss ◽  
Candidate Genes ◽  
Association Studies ◽  
Statistical Significance ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Cross Sectional ◽  
Time Points ◽  
Obese Subjects

Context and Objective: The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study. Methods: Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance. Results: In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2–4.2% (P < 10−14) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R2 = 0.4–1.1%; 3.8 × 10−6 < P < 3 × 10−3), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10−4 < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C. Conclusions: SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.

scholarly journals Oxytocin Administration Alleviates Acute but Not Chronic Leptin Resistance of Diet-Induced Obese Mice

2018 ◽  
Vol 20 (1) ◽  
pp. 88 ◽  
Author(s):  
Mehdi Labyb ◽  
Chloé Chrétien ◽  
Aurélie Caillon ◽  
Françoise Rohner-Jeanrenaud ◽  
Jordi Altirriba
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Leptin Resistance ◽  
Obese Mice ◽  
Short Term ◽  
Continuous Administration ◽  
Pre Treatment ◽  
Treatment Of Obesity

Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 μg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin.

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