A meta-analysis of photosynthetic efficiency and stress mitigation by melatonin in enhancing wheat tolerance.

BACKGROUND: Our meta-analysis examines the effects of melatonin on wheat under varying abiotic stress conditions, focusing on photosynthetic parameters, chlorophyll fluorescence, leaf water status, and photosynthetic pigments. We initially collected 177 publications addressing the impact of melatonin on wheat. After meticulous screening, 31 published studies were selected, encompassing 170 observations on photosynthetic parameters, 73 on chlorophyll fluorescence, 65 on leaf water status, 240 on photosynthetic pigments. RESULTS: The analysis revealed significant heterogeneity across studies (I² > 99.90%) for the aforementioned parameters and evidence of publication bias, emphasizing the complex interaction between melatonin application and plant physiological responses. Melatonin enhanced the overall response ratio (lnRR) for photosynthetic rates, stomatal conductance, transpiration rates, and fluorescence yields by 20.49, 22.39, 30.96, and 1.09%, respectively, compared to the control (no melatonin). The most notable effects were under controlled environmental conditions. Moreover, melatonin significantly improved leaf water content and reduced water potential, particularly under hydroponic conditions and varied abiotic stresses, highlighting its role in mitigating water stress. The analysis also revealed increases in chlorophyll pigments with soil drenching and foliar spray, and these were considered the effective application methods. Furthermore, melatonin influenced chlorophyll SPAD and intercellular CO2 concentrations, suggesting its capacity to optimize photosynthetic efficiency. CONCLUSIONS: This synthesis of meta-analysis confirms that melatonin significantly enhances wheat's resilience to abiotic stress by improving photosynthetic parameters, chlorophyll fluorescence, leaf water status, and photosynthetic pigments. Despite observed heterogeneity and publication bias, the consistent beneficial effects of melatonin, particularly under controlled conditions with specific application methods e.g. soil drenching and foliar spray, demonstrate its utility as a plant growth regulator for stress management. These findings encourage focused research and application strategies to maximize the benefits of melatonin in wheat farming, and thus contributing to sustainable agricultural practices.

Elucidating the modulatory effect of melatonin on enzyme activity and oxidative stress in wheat: a global meta-analysis.

In our comprehensive meta-analysis, we initially collected 177 publications focusing on the impact of melatonin on wheat. After meticulous screening, 40 published studies were selected, encompassing 558 observations for antioxidant enzymes, 312 for reactive oxygen species (ROS), and 92 for soluble biomolecules (soluble sugar and protein). This analysis revealed significant heterogeneity across studies (I2 > 99% for enzymes, ROS, and soluble biomolecules) and notable publication bias, indicating the complexity and variability in the research field. Melatonin application generally increased antioxidant enzyme activities [superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX)] in wheat, particularly under stress conditions, such as high temperature and heavy-metal exposure. Compared to control, melatonin application increased SOD, POD, CAT, and APX activities by 29.5, 16.96, 35.98, and 171.64%, respectively. Moreover, oxidative stress markers like hydrogen peroxide (H2O2), superoxide anion (O2), and malondialdehyde (MDA) decreased with melatonin by 23.73, 13.64, and 21.91%, respectively, suggesting a reduction in oxidative stress. The analysis also highlighted melatonin's role in improving carbohydrate metabolism and antioxidant defenses. Melatonin showed an overall increase of 12.77% in soluble sugar content, and 22.76% in glutathione peroxidase (GPX) activity compared to the control. However, the effects varied across different wheat varieties, environmental conditions, and application methods. Our study also uncovered complex relationships between antioxidant enzyme activities and H2O2 levels, indicating a nuanced regulatory role of melatonin in oxidative stress responses. Our meta-analysis demonstrates the significant role of melatonin in increasing wheat resilience to abiotic stressors, potentially through its regulatory impact on antioxidant defense systems and stress response.

Melatonin-Mediated Molecular Responses in Plants: Enhancing Stress Tolerance and Mitigating Environmental Challenges in Cereal Crop Production.

Cereal crops are crucial for global food security; however, they are susceptible to various environmental stresses that significantly hamper their productivity. In response, melatonin has emerged as a promising regulator, offering potential benefits for stress tolerance and crop growth. This review explores the effects of melatonin on maize, sorghum, millet, rice, barley, and wheat, aiming to enhance their resilience to stress. The application of melatonin has shown promising outcomes, improving water use efficiency and reducing transpiration rates in millet under drought stress conditions. Furthermore, it enhances the salinity and heavy metal tolerance of millet by regulating the activity of stress-responsive genes. Similarly, melatonin application in sorghum enhances its resistance to high temperatures, low humidity, and nutrient deficiency, potentially involving the modulation of antioxidant defense and aspects related to photosynthetic genes. Melatonin also exerts protective effects against drought, salinity, heavy metal, extreme temperatures, and waterlogging stresses in maize, wheat, rice, and barley crops by decreasing reactive oxygen species (ROS) production through regulating the antioxidant defense system. The molecular reactions of melatonin upregulated photosynthesis, antioxidant defense mechanisms, the metabolic pathway, and genes and downregulated stress susceptibility genes. In conclusion, melatonin serves as a versatile tool in cereal crops, bolstering stress resistance and promoting sustainable development. Further investigations are warranted to elucidate the underlying molecular mechanisms and refine application techniques to fully harness the potential role of melatonin in cereal crop production systems.

Catabolism of phenolics from grape peel and its effects on gut microbiota during in vitro colonic fermentation.

BACKGROUND: Grape peels, the main by-products of wine processing, are rich in bioactive ingredients of phenolics, including proanthocyanidins, flavonoids and anthocyanins. Phenolics have the function of regulating intestinal microbiota and promoting intestinal health. From the perspective of the dietary nutrition of grape peel phenolics (GPP), the present study aimed to investigate the influence of GPP on the composition and metabolism of human gut microbiota during in vitro fermentation. RESULTS: The results indicated that GPP could decrease pH and promote the production of short-chain fatty acids. ACE and Chao1 indices in GPP group were lower than that of the Blank group. GPP enhanced the levels of Lachnospiraceae UCG-004, Bacteroidetes and Roseburia, but reduced the Firmicutes/Bacteroidetes ratio. Kyoto Encyclopedia of Proteins and Genome enrichment pathways related to phenolic acid metabolism mainly included flavonoid, anthocyanin, flavone and flavonol biosynthesis. Gut microbiota could accelerate the release and breakdown of phenolic compounds, resulting in a decrease in the content of hesperetin-7-O-glucoside, delphinidin-3-O-glucoside and cyanidin-3-rutinoside etc. In vitro antibacterial test found that GPP increased the diameters of the inhibition zones of Escherichia coli and Staphylococcus aureus in a dose-dependent manner. CONCLUSION: The results of the present study revealed that GPP might be a potential prebiotic-like to prevent diseases by improving gut health. The findings could provide a theoretical basis for the potential to exploit GPP as dietary nutrition to maintain intestinal function. © 2024 Society of Chemical Industry.

YAP-dependent proliferation by a small molecule targeting annexin A2.

The transcriptional coactivator Yes-associated protein 1 (YAP) orchestrates a proproliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse following topical drug administration. Chemical proteomics revealed the relevant target of PY-60 to be annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase-bound, nonphosphorylated and transcriptionally active form of YAP. This work reveals ANXA2 as a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale to promote regenerative repair in disease.

Fungal Communities Are More Sensitive to the Simulated Environmental Changes than Bacterial Communities in a Subtropical Forest: the Single and Interactive Effects of Nitrogen Addition and Precipitation Seasonality Change.

Increased nitrogen deposition (N factor) and changes in precipitation patterns (W factor) can greatly impact soil microbial communities in tropical/subtropical forests. Although knowledge about the effects of a single factor on soil microbial communities is growing rapidly, little is understood about the interactive effects of these two environmental change factors. In this study, we investigated the responses of soil bacterial and fungal communities to the short-term simulated environmental changes (nitrogen addition, precipitation seasonality change, and their combination) in a subtropical forest in South China. The interaction between N and W factors was detected significant for affecting some soil physicochemical properties (such as pH, soil water, and NO3- contents). Fungi were more susceptible to treatment than bacteria in a variety of community traits (alpha, beta diversity, and network topological features). The N and W factors act antagonistically to affect fungal alpha diversity, and the interaction effect was detected significant for the dry season. The topological features of the meta-community (containing both bacteria and fungi) network overrode the alpha and beta diversity of bacterial or fungal communities in explaining the variation of soil enzyme activities. The associations between Ascomycota fungi and Gammaproteobacteria or Alphaproteobacteria might be important in mediating the inter-kingdom interactions. In summary, our results suggested that fungal communities were more sensitive to N and W factors (and their interaction) than bacterial communities, and the treatments' effects were more prominent in the dry season, which may have great consequences in soil processes and ecosystem functions in subtropical forests.

Effect of indel variants within the sorting nexin 29 (SNX29) gene on growth traits of goats.

The sorting nexin 29 gene (SNX29) is a well-known regulator of myocyte differentiation and proliferation. In this work, two indels (17-bp and 21-bp) were identified in the goat SNX29 gene, and their effects on the growth traits of 1,759 Shaanbei white cashmere (SBWC) goats were analyzed. Both indels had three genotypes [homozygote wild type (II), heterozygote (ID), and homozygote mutation (DD)] and displayed medium genetic diversity (0.25 < polymorphism information content (PIC) < 0.50) in the population. The 17-bp indel was significantly associated with chest width (p = 0.009), body weight (p = 0.021), and chest depth (p = 0.032), with the II genotype dominant. The 21-bp indel was significantly associated with chest width (p = 0.001), chest depth (p = 4.8E-5), heart girth (p = 0.007), and hip width (p = 0.002). Because the two indels were in the upstream (17-bp) and intron (21-bp) regions of the SNX29 gene, transcription factor binding sites were predicted. The IRF5 and MYC could bind with the 17-bp indel and 21-bp indel sequences, respectively. This study indicates that SNX29 is a promising candidate gene that can be used to improve meat production in goat breeding.

Molecular interaction site on procoagulant myosin for factor Xa-dependent prothrombin activation.

Skeletal muscle myosin has potent procoagulant activity that is based on its ability to enhance thrombin generation due to binding coagulation factors Xa and Va and accelerating prothrombin activation. A well-studied myosin inhibitor that binds to myosin's neck region inhibits myosin-dependent prothrombin activation. Hence, to identify a potential binding site(s) on skeletal muscle myosin for factor Xa, 19 peptides (25-40 residues) representing the neck region, which consists of a regulatory light chain, an essential light chain, and a heavy chain (HC), were screened for inhibition of myosin-supported prothrombin activation. Peptide HC796-835 comprising residues 796-835 of the heavy chain strongly inhibited myosin-enhanced prothrombin activation by factors Xa and Va (50% inhibition at 1.2 µm), but it did not inhibit phospholipid vesicle-enhanced prothrombin activation. Peptide inhibition studies also implicated several myosin light chain sequences located near HC796-835 as potential procoagulant sites. A peptide comprising HC796-835's C-terminal half, but not a peptide comprising its N-terminal half, inhibited myosin-enhanced prothrombin activation (50% inhibition at 1.2 µm). This inhibitory peptide (HC816-837) did not inhibit phospholipid-enhanced prothrombin activation, indicating its specificity for inhibition of myosin-dependent procoagulant mechanisms. Binding studies showed that purified factor Xa was bound to immobilized peptides HC796-835 and HC816-837 with apparent Kd values of 0.78 and 1.3 µm, respectively. In summary, these studies imply that HC residues 816-835 in the neck region of the skeletal muscle myosin directly bind factor Xa and, with contributions from light chain residues in this neck region, contribute to provision of myosin's procoagulant surface.

New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice.

Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural peptide reduces body weight in obese subjects and exhibits direct acute glucoregulatory effects in patients with type II diabetes. However, the clinical utility of OXM is limited due to its lower in vitro potency and short in vivo half-life. To overcome these issues, we developed stapled, long-acting, and highly potent OXM analogs with balanced activities at both GLP-1 and GCG receptors. The lead molecule O14 exhibits potent and long-lasting effects on glucose control, body weight loss, and reduction of hepatic fat reduction in DIO mice. Importantly, O14 significantly reversed hepatic steatosis; reduced liver weight, total cholesterol, and hepatic triglycerides; and improved markers of liver function in a nonalcoholic steatohepatitis (NASH) mouse model. A symmetrical version of the peptide was also shown to be more efficacious and long-lasting in controlling glucose than semaglutide and the clinical candidate cotadutide in wild-type mice, highlighting the utility of our designs of the dual agonist as a potential new therapy for diabetes and liver diseases.

Recombinant Expression and Stapling of a Novel Long-Acting GLP-1R Peptide Agonist.

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.

Effect of inclusion of HMBi in the ration of goats on feed intake, nutrient digestibility, rumen bacteria community and blood serum parameters.

The objective of this experiment was to test the effect of supplementation of analogues of methionine 2-hydroxy-4-methylthio butanoic acid isopropyl ester (HMBi) on growth, digestibility, antioxidant index, abundance and composition of rumen bacterial community in Xiangdong Black Goats. Thirty-six growing Xiangdong Black Goats were divided into four groups in such a way that each group had three replicate and each replicate had three animals. Experimental groups were assigned four levels of HMBi in basal diet: 0% HMBi (on dietary DM basis); 0.05% HMBi; 0.10% HMBi and 0.20% HMBi. Goats fed 0.10% HMBi in basal diet had higher average daily weight gain (p < .05). Goats fed 0.05% HMBi had higher apparent digestibility of gross energy (p < .01). The group 0% HMBi supplementation had a higher level of superoxide dismutase and malondialdehyde (p < .01). The goats fed 0.20% HMBi in basal diet had a higher level of insulin and leptin (p < .01) than 0% HMBi supplementation goats. 16S rRNA high-throughput sequencing analysis revealed similarities in the community composition, species diversity and relative abundance of dominant bacteria at the phylum and genus levels among the four groups. In conclusion, HMBi supplementation has no negative effect on apparent digestibility, antioxidant index and the ruminal bacteria composition. Therefore, 0.10% supplementation of HMBi is recommended in the diet of goats to improve the growth performance.

Design and Synthesis of Potent, Long-Acting Lipidated Relaxin-2 Analogs.

Peptide hormone relaxin-2, a member of the insulin family of peptides, plays a key role in hemodynamics and renal function and has shown preclinical efficacy in multiple disease models, including acute heart failure, fibrosis, preeclampsia, and corneal wound healing. Recently, serelaxin, a recombinant version of relaxin-2, has been studied in a large phase 3 clinical trial (RELAX-AHF-2) for acute decompensated heart failure patients with disappointing outcome. The poor in vivo half-life of relaxin-2 may have limited its therapeutic efficacy and long-term cardiovascular benefit. Herein, we have developed a semisynthetic methodology and generated potent, fatty acid-conjugated relaxin analogs with long-acting pharmacokinetic (PK) profile in rodents. The enhanced PK properties translated into improved and long-lasting pharmacodynamic effect in pubic ligament elongation (PLE) studies. The resultant novel relaxin analog, R9-13, represents the first long-acting relaxin-2 analog and could potentially improve the clinical efficacy and outcome for this important peptide hormone. This semisynthetic methodology could also be applied to other cysteine-rich peptides and proteins for half-life extension.

Underestimated ecosystem carbon turnover time and sequestration under the steady state assumption: A perspective from long-term data assimilation.

It is critical to accurately estimate carbon (C) turnover time as it dominates the uncertainty in ecosystem C sinks and their response to future climate change. In the absence of direct observations of ecosystem C losses, C turnover times are commonly estimated under the steady state assumption (SSA), which has been applied across a large range of temporal and spatial scales including many at which the validity of the assumption is likely to be violated. However, the errors associated with improperly applying SSA to estimate C turnover time and its covariance with climate as well as ecosystem C sequestrations have yet to be fully quantified. Here, we developed a novel model-data fusion framework and systematically analyzed the SSA-induced biases using time-series data collected from 10 permanent forest plots in the eastern China monsoon region. The results showed that (a) the SSA significantly underestimated mean turnover times (MTTs) by 29%, thereby leading to a 4.83-fold underestimation of the net ecosystem productivity (NEP) in these forest ecosystems, a major C sink globally; (b) the SSA-induced bias in MTT and NEP correlates negatively with forest age, which provides a significant caveat for applying the SSA to young-aged ecosystems; and (c) the sensitivity of MTT to temperature and precipitation was 22% and 42% lower, respectively, under the SSA. Thus, under the expected climate change, spatiotemporal changes in MTT are likely to be underestimated, thereby resulting in large errors in the variability of predicted global NEP. With the development of observation technology and the accumulation of spatiotemporal data, we suggest estimating MTTs at the disequilibrium state via long-term data assimilation, thereby effectively reducing the uncertainty in ecosystem C sequestration estimations and providing a better understanding of regional or global C cycle dynamics and C-climate feedback.

Design of Stapled Oxyntomodulin Analogs Containing Functionalized Biphenyl Cross-Linkers.

A panel of three lipid-modified, functionalized biphenyl cross-linkers (fBph) were synthesized and subsequently employed in the preparation of the stapled oxyntomodulin (OXM) analogs. In a luciferase-based reporter assay, these stapled OXM analogs showed varying degree of potency in activating GLP-1R and GCGR, presumably due to the disparate effect of the lipid chains on the local environment close to the ligand-receptor binding interface. In particular, the fBph-1 cross-linked peptide with the lipid chain attached to position-3 of the biphenyl cross-linker exhibited the highest dual agonist activity.

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery.

Antidiabetic treatments aiming to reduce body weight are currently gaining increased interest. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist administered twice daily via s.c. injection, improves glycemic control, often with associated weight reduction. To further improve the therapeutic efficacy of exendin-4, we have developed a novel peptide engineering strategy that incorporates a serum protein binding motif onto a covalent side-chain staple and applied to the peptide to enhance its helicity and, as a consequence, its potency and serum half-life. We demonstrated that one of the resulting peptides, E6, has significantly improved half-life and glucose tolerance in an oral glucose tolerance test in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism, and also reduced hepatic steatosis in diet-induced obese mice. Moreover, the high potency of E6 allowed us to administer this peptide using a dissolvable microstructure-based transdermal delivery system. Pharmacokinetic and pharmacodynamic studies in guinea pigs showed that a single 5-min application of a microstructure system containing E6 significantly improved glucose tolerance for 96 h. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones.

Uncovering C4-like photosynthesis in C3 vascular cells.

In C4 plants, the vascularization of the leaf is extended to include a ring of photosynthetic bundle sheath cells, which have essential and specific functions. In contrast to the substantial knowledge of photosynthesis in C4 plants, relatively little is known about photosynthesis in C3 plant veins, which differs substantially from that in C3 mesophyll cells. In this review we highlight the specific photosynthetic machinery present in C3 vascular cells, which likely evolved prior to the divergence between C3 and C4 plants. The associated primary processes of carbon recapture, nitrogen transport, and antioxidant metabolism are discussed. This review of the basal C4 photosynthesis in C3 plants is significant in the context of promoting the potential for biotechnological development of C4-transgenic rice crops.

Overcoming resistance to HER2 inhibitors through state-specific kinase binding.

The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic, but recent studies have demonstrated that stimulating the heterodimeric complex, either via growth factors or by increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes the activity of the inhibitors. To identify an inhibitor of the active HER2-HER3 oncogenic complex, we developed a panel of Ba/F3 cell lines suitable for ultra-high-throughput screening. Medicinal chemistry on the hit scaffold resulted in a previously uncharacterized inhibitor that acts through preferential inhibition of the active state of HER2 and, as a result, is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.

Soil mineral alters the effect of Cd on the alkaline phosphatase activity.

The toxicity of heavy metals (HMs) to soil enzymes is directly influenced by the status of the enzyme (free vs. immobilized on minerals) and the duration of exposure. However, little information is available on the interaction effect of HMs, mineral, and exposure time on soil enzyme activities. We investigated the interaction mechanism of alkaline phosphatase (ALP) with minerals (montmorillonite and goethite) and the response of free and immobilized ALP to cadmium (Cd) toxicity under different exposure times. The adsorption isotherms of ALP on both minerals were L-type. The maximum adsorption capacity of goethite for ALP was 3.96 times than montmorillonite, although both had similar adsorption constant (K). Goethite showed a greater inhibitory effect on ALP activity than montmorillonite. The toxicity of Cd to free- and goethite-ALP was enhanced with increasing exposure time, indicating a time-dependent inhibition. However, Cd toxicity to montmorillonite-ALP was not affected by the exposure time. The inhibition of Cd to soil enzyme activity is influenced by the properties of mineral complexes and the duration of exposure. A further understanding of the time pattern of HMs toxicity is helpful for accurately assessing the hazards of HMs to soil enzyme activity.

Oxysterols direct immune cell migration via EBI2.

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3ß,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.

Multifunctional Antibody Agonists Targeting Glucagon-like Peptide-1, Glucagon, and Glucose-Dependent Insulinotropic Polypeptide Receptors.

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), glucagon (GCG) receptor (GCGR), and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor (GIPR), are three metabolically related peptide hormone receptors. A novel approach to the generation of multifunctional antibody agonists that activate these receptors has been developed. Native or engineered peptide agonists for GLP-1R, GCGR, and GIPR were fused to the N-terminus of the heavy chain or light chain of an antibody, either alone or in pairwise combinations. The fusion proteins have similar in vitro biological activities on the cognate receptors as the corresponding peptides, but circa 100-fold longer plasma half-lives. The GLP-1R mono agonist and GLP-1R/GCGR dual agonist antibodies both exhibit potent effects on glucose control and body weight reduction in mice, with the dual agonist antibody showing enhanced activity in the latter.