TY  - JOUR
AB  - In recent years, significant progress has been made to pharmacologically combat the obesity pandemic, particularly with regard to biochemically tailored drugs that simultaneously target the receptors for glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP). But while the pharmacological benefits of GLP-1 receptor (GLP-1R) agonism are widely acknowledged, the role of the GIP system in regulating systems metabolism remains controversial. When given in adjunct to GLP-1R agonism, both agonism and antagonism of the GIP receptor (GIPR) improves metabolic outcome in preclinical and clinical studies, and despite persistent concerns about its potential obesogenic nature, there is accumulating evidence indicating that GIP has beneficial metabolic effects via central GIPR agonism. Nonetheless, despite growing recognition of the GIP system as a valuable pharmacological target, there remains great uncertainty as to where and how GIP acts in the brain to regulate metabolism, and how GIPR agonism may differ from GIPR antagonism in control of energy metabolism. In this review we highlight current knowledge on the central action of GIP, and discuss open questions related to its multifaceted biology in the brain and the periphery.
AU  - Liskiewicz, A.
AU  - Müller, T.D.
C1  - 70400
C2  - 55605
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Regulation of energy metabolism through central GIPR signaling.
JO  - Peptides
VL  - 176
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - The number of diabetic patients is rising globally and concomitantly so do the diabetes associated complications. The gut secretes a variety of proteins to control blood glucose levels and/or food intake. As the drug class of GLP-1 agonists is based on a gut secreted peptide and the positive metabolic effects of bariatric surgery are at least partially mediated by gut peptides, we were interested in other gut secreted proteins which have yet to be explored. In this respect we identified the gut secreted protein FAM3D by analyzing sequencing data from L- and epithelial cells of VSG and sham operated as well as chow and HFD fed mice. FAM3D was overexpressed in diet induced obese mice via an adeno-associated virus (AAV), which resulted in a significant improvement of fasting blood glucose levels, glucose tolerance and insulin sensitivity. The liver lipid deposition was reduced, and the steatosis morphology was improved. Hyperinsulinemic clamps indicated that FAM3D is a global insulin sensitizer and increases glucose uptake into various tissues. In conclusion, the current study demonstrated that FAM3D controls blood glucose levels by acting as an insulin sensitizing protein and improves hepatic lipid deposition.
AU  - Moser, C.*
AU  - Gosselé, K.A.*
AU  - Balaz, M.*
AU  - Balázová, L.*
AU  - Horvath, C.*
AU  - Künzle, P.*
AU  - Okreglicka, K.M.*
AU  - Li, F.*
AU  - Blüher, M.
AU  - Stierstorfer, B.*
AU  - Hess, E.*
AU  - Lamla, T.*
AU  - Hamilton, B.*
AU  - Klein, H.*
AU  - Neubauer, H.*
AU  - Wolfrum, C.*
AU  - Wolfrum, S.*
C1  - 68464
C2  - 54683
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - FAM3D: A gut secreted protein and its potential in the regulation of glucose metabolism.
JO  - Peptides
VL  - 167
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - Within recent decades glucagon receptor (GcgR) agonism has drawn attention as a therapeutic tool for the treatment of type 2 diabetes and obesity. In both mice and humans, glucagon administration enhances energy expenditure and suppresses food intake suggesting a promising metabolic utility. Therefore synthetic optimization of glucagon-based pharmacology to further resolve the physiological and cellular underpinnings mediating these effects has advanced. Chemical modifications to the glucagon sequence have allowed for greater peptide solubility, stability, circulating half-life, and understanding of the structure-function potential behind partial and "super"-agonists. The knowledge gained from such modifications has provided a basis for the development of long-acting glucagon analogues, chimeric unimolecular dual- and tri-agonists, and novel strategies for nuclear hormone targeting into glucagon receptor-expressing tissues. In this review, we summarize the developments leading toward the current advanced state of glucagon-based pharmacology, while highlighting the associated biological and therapeutic effects in the context of diabetes and obesity.
AU  - Novikoff, A.
AU  - Müller, T.D.
C1  - 67644
C2  - 53951
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - The molecular pharmacology of glucagon agonists in diabetes and obesity.
JO  - Peptides
VL  - 165
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - Calcitonin Gene-Related Peptide (CGRP) is a potent vasodilator peptide widely distributed in the central nervous system and various peripheral tissues, including cardiac muscle. However, its role in heart protein metabolism remains unknown. We examined the acute effects of CGRP on autophagy and the related signaling pathways in the heart mice and cultured neonatal cardiomyocytes. CGRP (100 μg kg−1; s.c.) or 0.9 % saline was injected in awake male C57B16 mice, and the metabolic profile was determined up to 60 min. In fed mice, CGRP drastically increased glycemia and reduced insulinemia, an effect that was accompanied by reduced cardiac phosphorylation levels of Akt at Ser473 without affecting FoxO. Despite these catabolic effects, CGRP acutely inhibited autophagy as estimated by the decrease in LC3II:LC3I and autophagic flux. In addition, the fasting-induced autophagic flux in mice hearts was entirely abrogated by one single injection of CGRP. In parallel, CGRP stimulated PKA/CREB and mTORC1 signaling and increased the phosphorylation of Unc51-like kinase-1 (ULK1), an essential protein in autophagy initiation. Similar effects were observed in cardiomyocytes, in which CGRP also inhibited autophagic flux and stimulated Akt and FoxO phosphorylation. These findings suggest that CGRP in vivo acutely suppresses autophagy in the heart of fed and fasted mice, most likely through the activation of PKA/mTORC1 signaling but independent of Akt.
AU  - Schavinski, A.Z.*
AU  - Machado, J.
AU  - Morgan, H.J.N.*
AU  - Lautherbach, N.*
AU  - Paula-Gomes, S.*
AU  - Kettelhut, I.C.*
AU  - Navegantes, L.C.C.*
C1  - 63372
C2  - 51491
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Calcitonin gene-related peptide exerts inhibitory effects on autophagy in the heart of mice.
JO  - Peptides
VL  - 146
PB  - Elsevier Science Inc
PY  - 2021
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - The gastric inhibitory polypeptide receptor (GIPR) regulates postprandial metabolism. In this context GIPR SNP rs10423928 seems toplay an important role in modulating glucose metabolism and insulinsensitivity. However, evidence regarding thisparticular SNP is still vague.In this study, we collected baseline data from four different dietaryintervention studies. We genotyped 424 subjects with prediabetes and 73with diabetes for GIPR SNP rs10423928 and examined its impact on glucosemetabolism, insulin sensitivity and body fat accumulation.We extended previous data by showing that carriers of the A allele withprediabetes displayed increased fasting glucose (p = 0.015). Unexpectedly,A allele carriers showed lower glucose levels 2 h (p = 0.021) after anoral glucose challenge compared to T/T homozygous individuals. A allelecarriers also showed significantly higher insulin sensitivity (p < 0.001)(assessed by Cederholm Index), indicating an enhanced beta-cell response.This study points to a potential protective role for rs10423928 inglucose metabolism and insulin sensitivity in subjects with prediabetes.Further studies are necessary to confirm these results.
AU  - Barbosa-Yañez, R.L.*
AU  - Markova, M.*
AU  - Dambeck, U.*
AU  - Honsek, C.*
AU  - Machann, J.
AU  - Schüler, R.*
AU  - Kabisch, S.*
AU  - Pfeiffer, A.F.H.*
C1  - 57794
C2  - 47961
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Predictive effect of GIPR SNP rs10423928 on glucose metabolism liver fat and adiposity in prediabetic and diabetic subjects.
JO  - Peptides
VL  - 125
PB  - Elsevier Science Inc
PY  - 2020
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical stages of drug development. A priority has been anti-obesity unimolecular peptides that function as balanced, high potency poly-agonists at two or all the cellular receptors for the endocrine hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. This report reviews recent progress in this area, with emphasis on what the initial clinical results demonstrate and what remains to be addressed.
AU  - Knerr, P.J.*
AU  - Mowery, S.A.*
AU  - Finan, B.*
AU  - Perez-Tilve, D.*
AU  - Tschöp, M.H.
AU  - DiMarchi, R.D.*
C1  - 57711
C2  - 47882
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates.
JO  - Peptides
VL  - 125
PB  - Elsevier Science Inc
PY  - 2020
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - Chemical derivatives of the gut-derived peptide hormone glucagon-like peptide 1 (GLP-1) are among the best-in-class pharmacotherapies to treat obesity and type 2 diabetes. However, GLP-1 analogs have modest weight lowering capacity, in the range of 5-10%, and the therapeutic window is hampered by dose-dependent side effects. Over the last few years, a new concept has emerged: combining the beneficial effects of several key metabolic hormones into a single molecular entity. Several unimolecular GLP-1-based polyagonists have shown superior metabolic action compared to GLP-1 monotherapies. In this review article, we highlight the history of polyagonists targeting the receptors for GLP-1, GIP and glucagon, and discuss recent progress in expanding of this concept to now allow targeted delivery of nuclear hormones via GLP-1 and other gut hormones, as a novel approach towards more personalized pharmacotherapies.
AU  - Brandt, S.
AU  - Götz, A.
AU  - Tschöp, M.H.
AU  - Müller, T.D.
C1  - 52908
C2  - 44382
CY  - New York
SP  - 190-201
TI  - Gut hormone polyagonists for the treatment of type 2 diabetes.
JO  - Peptides
VL  - 100
PB  - Elsevier Science Inc
PY  - 2018
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - In the treatment of insulin-dependent diabetes the risk of a fatal insulin overdose is a persistent fear to most patients. In order to potentially reduce the risk of overdose, we report the design, synthesis, and biochemical characterization of a set of insulin analogs designed to be fractionally reduced in maximal agonism at the insulin receptor isoforms. These analogs consist of native insulin that is site-specifically conjugated to a peptide-based insulin receptor antagonist. The structural refinement of the antagonist once conjugated to insulin provided a set of partial agonists exhibiting between 25 and 70% of the maximal agonism of native insulin at the two insulin receptor isoforms, with only slight differences in inherent potency. These rationally-designed partial agonists provide an approach to interrogate whether control of maximal activity can provide glycemic control with reduced hypoglycemic risk.
AU  - Brandt, S.
AU  - Mayer, J.P.*
AU  - Ford, J.*
AU  - Gelfanov, V.M.*
AU  - DiMarchi, R.D.*
C1  - 52909
C2  - 44623
SP  - 18-23
TI  - Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity.
JO  - Peptides
VL  - 100
PY  - 2018
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - The a 28-amino acid peptide ghrelin was discovered in 1999 as a growth hormone (GH) releasing peptide. Soon after its discovery, ghrelin was found to increase body weight and adiposity by acting on the hypothalamic melanocortinergic system. Subsequently, ghrelin was found to exert a series of metabolic effects, overall testifying ghrelin a pleiotropic nature of broad pharmacological interest. Ghrelin acts through the growth hormone secretagogue-receptor (GHS-R), a seven transmembrane G protein-coupled receptor with high expression in the anterior pituitary, pancreatic islets, thyroid gland, heart and various regions of the brain. Among ghrelins numerous metabolic effects are the most prominent the stimulation of appetite via activation of orexigenic hypothalamic neurocircuits and the food-intake independent stimulation of lipogenesis, which both together lead to an increase in body weight and adiposity. Ghrelin effects beyond the regulation of appetite and GH secretion include the regulation of gut motility, sleep-wake rhythm, taste sensation, reward seeking behaviour, and the regulation of glucose metabolism. The latter received recently increasing recognition because pharmacological inhibition of ghrelin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes. In this review we highlight the multifaceted nature of ghrelin and summarize its glucoregulatory action and discuss the pharmacological value of ghrelin pathway inhibition for the treatment of glucose intolerance and type 2 diabetes.
AU  - Poher, A.-L.
AU  - Tschöp, M.H.
AU  - Müller, T.D.
C1  - 52907
C2  - 44383
CY  - New York
SP  - 236-242
TI  - Ghrelin regulation of glucose metabolism.
JO  - Peptides
VL  - 100
PB  - Elsevier Science Inc
PY  - 2018
SN  - 0196-9781
ER  - 

TY  - JOUR
AB  - The hypothalamic neuropeptide orexin A (hypocretin-1) is a key signal in sleep/wake regulation and promotes food intake. We investigated the relationship between cerebrospinal fluid orexin A concentrations and body composition in non-narcoleptic human subjects with a wide range of body weight to gain insight into the role of orexin A in human metabolism. We collected cerebrospinal fluid and blood samples and measured body composition by bioelectric impedance analysis in 36 subjects (16 women and 20 men) with body mass indices between 16.24 and 38.10 kg/mand an age range of 19-80 years. Bivariate Pearson correlations and stepwise multiple regressions were calculated to determine associations between orexin A and body composition as well as biometric variables. Concentrations of orexin A in cerebrospinal fluid averaged 315.6 ± 6.0 pg/ml, were comparable between sexes (p > 0.15) and unrelated to age (p > 0.66); they appeared slightly reduced in overweight/obese compared to normal-weight subjects (p = .07). Orexin A concentrations decreased with body weight (r = -0.38, p = .0229) and fat-free mass (r = -0.39, p = .0173) but were not linked to body fat mass (p > 0.24). They were inversely related to total body water (r = -0.39, p = .0174) as well as intracellular (r = -0.41, p = .0139) and extracellular water (r = -0.35, p = .0341). Intracellular water was the only factor independently associated with cerebrospinal fluid orexin A concentrations (p = .0139). We conclude that cerebrospinal fluid orexin A concentrations do not display associations with body adiposity, but are inversely related to intracellular water content. These cross-sectional findings suggest a link between orexin A signaling and the regulation of water homeostasis in humans.
AU  - Santiago, J.C.
AU  - Otto, M.*
AU  - Kern, W.*
AU  - Baier, P.C.*
AU  - Hallschmid, M.
C1  - 53040
C2  - 44447
SP  - 26-30
TI  - Relationship between cerebrospinal fluid concentrations of orexin A/hypocretin-1 and body composition in humans.
JO  - Peptides
VL  - 102
PY  - 2018
SN  - 0196-9781
ER  -