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Hole U1395B, drilled southeast of Montserrat during Integrated Ocean Drilling Program Expedition 340, provides a long (>1 Ma) and detailed record of eruptive and mass-wasting events (>130 discrete events). This record can be used to explore the temporal evolution in volcanic activity and landslides at an arc volcano. Analysis of tephra fall and volcaniclastic turbidite deposits in the drill cores reveals three heightened periods of volcanic activity on the island of Montserrat (∼930 to ∼900 ka, ∼810 to ∼760 ka, and ∼190 to ∼120 ka) that coincide with periods of increased volcano instability and mass-wasting. The youngest of these periods marks the peak in activity at the Soufrière Hills volcano. The largest flank collapse of this volcano (∼130 ka) occurred toward the end of this period, and two younger landslides also occurred during a period of relatively elevated volcanism. These three landslides represent the only large (>0.3 km3) flank collapses of the Soufrière Hills edifice, and their timing also coincides with periods of rapid sea level rise (>5 m/ka). Available age data from other island arc volcanoes suggest a general correlation between the timing of large landslides and periods of rapid sea level rise, but this is not observed for volcanoes in intraplate ocean settings. We thus infer that rapid sea level rise may modulate the timing of collapse at island arc volcanoes, but not in larger ocean-island settings.

Understanding terrestrial carbon metabolism is critical because terrestrial ecosystems play a major role in the global carbon cycle. Furthermore, humans have severely disrupted the carbon cycle in ways that will alter the climate system and directly affect terrestrial metabolism. Changes in terrestrial metabolism may well be as important an indicator of global change as the changing temperature signal. Improving our understanding of the carbon cycle at various spatial and temporal scales will require the integration of multiple, complementary and independent methods that are used by different research communities. Tools such as air sampling networks, inverse numerical methods, and satellite data (top-down approaches) allow us to study the strength and location of the global- and continental-scale carbon sources and sinks. Bottom-up studies provide estimates of carbon fluxes at finer spatial scales and examine the mechanisms that control fluxes at the ecosystem, landscape, and regional scales. Bottom-up approaches include comparative and process studies (for example, ecosystem manipulative experiments) that provide the necessary mechanistic information to develop and validate terrestrial biospheric models. An iteration and reiteration of top-down and bottom-up approaches will be necessary to help constrain measurements at various scales. We propose a major international effort to coordinate and lead research programs of global scope of the carbon cycle.

Understanding terrestrial carbon metabolism is critical because terrestrial ecosystems play a major role in the global carbon cycle. Furthermore, humans have severely disrupted the carbon cycle in ways that will alter the climate system and directly affect terrestrial metabolism. Changes in terrestrial metabolism may well be as important an indicator of global change as the changing temperature signal. Improving our understanding of the carbon cycle at various spatial and temporal scales will require the integration of multiple, complementary and independent methods that are used by different research communities. Tools such as air sampling networks, inverse numerical methods, and satellite data (top-down approaches) allow us to study the strength and location of the global- and continental-scale carbon sources and sinks. Bottom-up studies provide estimates of carbon fluxes at finer spatial scales and examine the mechanisms that control fluxes at the ecosystem, landscape, and regional scales. Bottom-up approaches include comparative and process studies (for example, ecosystem manipulative experiments) that provide the necessary mechanistic information to develop and validate terrestrial biospheric models. An iteration and reiteration of top-down and bottom-up approaches will be necessary to help constrain measurements at various scales. We propose a major international effort to coordinate and lead research programs of global scope of the carbon cycle.

Abstract Background Plasmodium berghei ookinetes exhibit an apoptotic phenotype when developing within the mosquito midgut lumen or when cultured in vitro. Markers of apoptosis increase when they are exposed to nitric oxide or reactive oxygen species but high concentrations of hydrogen peroxide cause death without observable signs of apoptosis. Chloroquine and other drugs have been used to induce apoptosis in erythrocytic stages of Plasmodium falciparum and to formulate a putative pathway involving cysteine protease activation and mitochondrial membrane permeabilization; initiated, at least in the case of chloroquine, after its accumulation in the digestive vacuole causes leakage of the vacuole contents. The lack of a digestive vacuole in ookinetes prompted the investigation of the effect of chloroquine and staurosporine on this stage of the life cycle. Finally, the suggestion that apoptosis may have evolved as a strategy employed by ookinetes to increase the fitness of surviving parasites was explored by determining whether increasing the ecological triggers parasite density and nutrient depletion induced apoptosis. Methods Ookinetes were grown in culture then either exposed to hydrogen peroxide, chloroquine or staurosporine, or incubated at different densities and in different media. The proportion of ookinetes displaying positive markers for apoptosis in treated samples was compared with controls and results were analyzed using analysis of variance followed by a Turkey’s test, or a Kruskal-Wallis test as appropriate. Results Hydrogen peroxide below 50 μM triggered apoptosis but cell membranes were rapidly compromised by higher concentrations, and the mode of death could not be defined. Both chloroquine and staurosporine cause a significant increase in ookinetes with condensed chromatin, caspase-like activity and, in the case of chloroquine, phosphatidylserine translocation and DNA fragmentation (not investigated for staurosporine). However, mitochondrial membrane potential remained intact. No relationship between ookinete density and apoptosis was detected but nutrient depletion significantly increased the proportion of ookinetes with chromatin condensation in four hours. Conclusions It is proposed that both a mitochondrial and an amitochondrial apoptotic pathway may be involved, dependent upon the trigger that induces apoptosis, and that pathways may differ between erythrocytic stages and ookinetes, or between rodent and human malaria parasites.

Abstract Background Aboriginal and Torres Strait Islander peoples are under-reported in administrative health datasets in NSW, Australia. Correct reporting of Aboriginal and Torres Strait Islander peoples is essential to measure the effectiveness of policies and programmes aimed at reducing the health disadvantage experienced by Aboriginal and Torres Strait Islander peoples. This study investigates the potential of record linkage to enhance reporting of deaths among Aboriginal and Torres Strait Islander peoples in NSW, Australia. Methods Australian Bureau of Statistics death registration data for 2007 were linked with four population health datasets relating to hospitalisations, emergency department attendances and births. Reporting of deaths was enhanced from linked records using two methods, and effects on patterns of demographic characteristics and mortality indicators were examined. Results Reporting of deaths increased by 34.5% using an algorithm based on a weight of evidence of a person being Aboriginal or Torres Strait Islander, and by 56.6% using an approach based on 'at least one report' of a person being Aboriginal or Torres Strait Islander. The increase was relatively greater in older persons and those living in less geographically remote areas. Enhancement resulted in a reduction in the urban-remote differential in median age at death and increases in standardised mortality ratios particularly for chronic conditions. Conclusions Record linkage creates a statistical construct that helps to correct under-reporting of deaths and potential bias in mortality statistics for Aboriginal and Torres Strait Islander peoples.

It has been long known that people with schizophrenia (SZ) have deficits in perceptual processing, including in the auditory domain. Furthermore, they often experience increased emotional responsivity and dysregulation, which further impacts overall functioning. Increased emotional responsivity to auditory stimuli is also seen in people with misophonia, a condition in which specific sounds elicit robust negative emotional responses. Given the role of emotional reactivity and dysregulation in the pathogenesis of SZ, our study investigated whether misophonia symptoms were elevated in SZ, or if people with SZ have a generalized increase in reactivity to sensory information. To explore the link between emotional reactivity to sound and more general aspects emotional reactivity and salience signaling in SZ, we used the Misophonia Questionnaire, the Sensory Processing Scale (SPS), and Aberrant Salience Inventory (ASI) in 30 people with SZ and 28 demographically-matched healthy volunteers (HVs). We found that people with SZ exhibited more emotional behavior associated with misophonia symptoms (specifically, distress in relation to sound) than HVs (t 56  = 4.889, p < 0.001), but did not have elevated rates of misophonia overall. Also, sensory processing abnormalities and heightened emotional responses in people with SZ were not limited to the auditory domain but, rather, extended to all sensory modalities. Our results support the idea that SZ involves dysfunction in salience signaling, regarding auditory stimuli, but that abnormalities in salience signaling in SZ are more domain-general. These results highlight the importance of interventions designed to enhance emotion regulation in patients with SZ regarding stimuli in multiple modalities., Competing Interests: Declaration of competing interest DLK consults for Alkermes PLC, Karuna Neuroscience, and Janssen Pharmaceuticals, but these relationships played no role in the study design and/or interpretation of the present study's results. None of the authors have any financial conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We tested an approach to estimate daily canopy net photosynthesis, A, based on estimates of transpiration, E, using measurements of sap flow and water-use efficiency, ω, by measuring δ13C in CO2 respired from shoots in the canopies of two conifers (Podocarpaceae) native to New Zealand. The trees were planted in adjacent 20-year-old stands with the same soil and environmental conditions. Leaf area index was lower for Dacrycarpus dacrydioides D.Don in Lamb (1.34 m2 m-2) than for Podocarpus totara G.Benn. ex D.Don var. totara (2.01 m2 m-2), but mean (± standard error) stem diameters were the same at 152 ± 21 mm for D. dacrydioides and 154 ± 25 mm for P. totara. Over a 28-day period, daily A (per unit ground area) ranged almost five-fold but there were no significant differences between species (mean 2.73 ± 1.02 gC m-2 day-1). This was attributable to higher daily values of E (2.63 ± 0.83 mm day-1) and lower ω (1.35 ± 0.53 gC kg H2O-1) for D. dacrydioides compared with lower E (1.82 ± 0.72 mm day-1) and higher ω (1.90 ± 0.77 gC kg H2O-1) for P. totara. We attributed this to higher nitrogen availability and nitrogen concentration per unit foliage area, Na, and greater exposure to irradiance in the D. dacrydioides canopy compared with P. totara. Our findings support earlier observations that D. dacrydioides is more adapted to sites with poor drainage. In contrast, the high retention of leaf area and maintaining low rates of transpiration by P. totara, resulting in higher water-use efficiency, is an adaptive response to survival in dry conditions. Our findings show that physiological adjustments for two species adapted to different environments led to similar canopy photosynthesis rates when the trees were grown in the same conditions. We demonstrated consistency between whole-tree and more intensive shoot-scale measurements, confirming that integrated approaches are appropriate for comparative estimates of carbon uptake in stands with different species., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Short-chain fatty acids (SCFAs) are the major microbial metabolites produced from the fermentation of dietary fiber in the gut. They are recognised as secretagogues of the glucagon-like peptides, GLP-1 and GLP-2, likely mediated by the activation of free fatty acid receptors 2 and 3 (FFAR2 and 3) expressed on enteroendocrine L-cells. Fiber-deficient diets are associated with decreased intestinal function and decreased colonic GLP-1 and GLP-2 content. Here, we speculated that the lowered colonic GLP-1 observed following a fiber-free diet was a consequence of decreased SCFA production and a subsequent decrease in FFAR2/3 activation. Furthermore, we explored the consequences of a fiber-free diet followed by intestinal injury, and we mechanistically explored the SCFA-FFAR2/3-GLP-1 pathway to explain the increased severity. Colonic luminal content from mice fed either a fiber-free or chow diet were analysed for SCFA content by LC-MS. FFAR2/3 receptor contributions to SCFA-mediated colonic GLP-1 secretion were assessed in isolated perfused preparations of the colon from FFAR2/3 double knockout (KO) and wild-type (WT) mice. Colitis was induced by the delivery of 3% dextran sulfate sodium (DSS) for 4 days in the drinking water of mice exposed to a fiber-free diet for 21 days. Colitis was induced by the delivery of 3% DSS for 7 days in FFAR2/3 KO mice. The removal of dietary fiber significantly decreased SCFA concentrations in the luminal contents of fiber-free fed mice compared to chow-fed mice. In the perfused colon, luminal SCFAs significantly increased colonic GLP-1 secretion in WT mice but not in FFAR2/3 KO mice. In the DSS-induced colitis model, the removal of dietary fiber increased the severity and prevented the recovery from intestinal injury. Additionally, colitis severity was similar in FFAR2/3 KO and WT mice after DSS application. In conclusion, the results confirm that the removal of dietary fiber is sufficient to decrease the colonic concentrations of SCFAs. Additionally, we show that a fiber-free diet predisposes the colon to increased intestinal injury, but this effect is independent of FFAR2 and FFAR3 signalling; therefore, it is unlikely that a fiber-free diet induces a decrease in luminal SCFAs and sensitivity to intestinal disease involves the SCFA-FFAR2/3-GLP-1 pathway.

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD., Competing Interests: RT reports research funding to Georgetown University from Alector, Biogen, Cognition Therapeutics, Eisai, Janssen, Lilly, Roche/Genentech, Vaccinex, and Vivoryon. RT is a consultant to Re: Cognition Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yap, Hunt and Turner.)

Objective: Fiber-free diet impairs intestinal and colonic health in mice, in parallel with a reduction in glucagon like peptide-1 (GLP-1) levels. Endogenous GLP-1 is important for intestinal growth and maintenance of the intestinal integrity. We aimed to investigate whether fiber-free diet reduces luminal content of metabolites which, upon supplementation, could increase GLP-1 secretion and restore the adverse effects of fiber-free diet., Methods: Untargeted metabolomics (LC-MS) was performed on colonic content of mice fed a fiber-free diet, identifying a metabolite of particular interest: indole-3-carboxyaldehyde (I3A). We exposed cultured GLUTag cells to I3A, and measured cumulative GLP-1 secretion. Isolated colon perfusions were performed in male C57BL/6JRj mice and Wistar rats. I3A was administered luminally or vascularly, and GLP-1 was measured in portal vein effluent. Finally, female C57BL/6JRJ mice were fed chow or fiber-free diet, with I3A or vehicle by oral gavage. After 10 days, plasma GLP-1 (ELISA) and intestinal permeability (FITC-dextran) were measured, animals were sacrificed and organs removed for histology., Results: Mice fed a fiber-free diet had significantly lower I3A in their colonic content compared to a control diet (7883 ± 3375 AU, p =0.04). GLP-1 secretion from GLUTag cells was unchanged after five minutes of exposure to I3A. However, GLP-1 levels increased after 120 minutes of exposure to 1 mM (60% increase, p =0.016) and 5 mM (89% increase, p =0.0025) I3A. In contrast, 48 h exposure to 1 mM decreased GLP-1 secretion (51% decrease, p< 0.001) and viability. In isolated perfused mouse and rat colon, I3A applied into the luminal or vascular side did not affect GLP-1 secretion. Mice fed a fiber-free diet tended to weigh less compared to chow fed mice; and the small intestine and colon were significantly smaller. No differences were seen in crypt depth, villus length, mucosal area, and intestinal permeability. Supplementing I3A did not affect body weight, morphology or plasma GLP-1 levels., Conclusions: Fiber-free diet lowered colonic content of I3A in mice. I3A stimulates GLP-1 secretion in vitro , but not in animal studies. Moreover, it has no evident beneficial effect on intestinal health when administered in vivo ., Competing Interests: JJH: Advisory boards: Novo Nordisk; Lecture fees: Novo Nordisk; Merck. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Smits, Dreyer, Hunt, Drzazga, Modvig, Holst and Kissow.)

Background: By examining species-specific innate behaviours, neuroethologists have characterized unique neural strategies and specializations from throughout the animal kingdom. Simultaneously, the field of evolutionary developmental biology (informally, "evo-devo") seeks to make inferences about animals' evolutionary histories through careful comparison of developmental processes between species, because evolution is the evolution of development. Yet despite the shared focus on cross-species comparisons, there is surprisingly little crosstalk between these two fields. Insights can be gleaned at the intersection of neuroethology and evo-devo. Every animal develops within an environment, wherein ecological pressures advantage some behaviours and disadvantage others. These pressures are reflected in the neurodevelopmental strategies employed by different animals across taxa., Summary: Vision is a system of particular interest for studying the adaptation of animals to their environments. The visual system enables a wide variety of animals across the vertebrate lineage to interact with their environments, presenting a fantastic opportunity to examine how ecological pressures have shaped animals' behaviours and developmental strategies. Applying a neuroethological lens to the study of visual development, we advance a novel theory that accounts for the evolution of spontaneous retinal waves, an important phenomenon in the development of the visual system, across the vertebrate lineage., Key Messages: We synthesize literature on spontaneous retinal waves from across the vertebrate lineage. We find that ethological considerations explain some cross-species differences in the dynamics of retinal waves. In zebrafish, retinal waves may be more important for the development of the retina itself, rather than the retinofugal projections. We additionally suggest empirical tests to determine whether Xenopus laevis experiences retinal waves., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The impacts of large terrestrial volcanic eruptions are apparent from satellite monitoring and direct observations. However, more than three quarters of all volcanic outputs worldwide lie submerged beneath the ocean, and the risks they pose to people, infrastructure, and benthic ecosystems remain poorly understood due to inaccessibility and a lack of detailed observations before and after eruptions. Here, comparing data acquired between 2015 - 2017 and 3 months after the January 2022 eruption of Hunga Volcano, we document the far-reaching and diverse impacts of one of the most explosive volcanic eruptions ever recorded. Almost 10 km 3 of seafloor material was removed during the eruption, most of which we conclude was redeposited within 20 km of the caldera by long run-out seafloor density currents. These powerful currents damaged seafloor cables over a length of >100 km, reshaped the seafloor, and caused mass-mortality of seafloor life. Biological (mega-epifaunal invertebrate) seafloor communities only survived the eruption where local topography provided a physical barrier to density currents (e.g., on nearby seamounts). While the longer-term consequences of such a large eruption for human, ecological and climatic systems are emerging, we expect that these previously-undocumented refugia will play a key role in longer-term ecosystem recovery., (© 2023. The Author(s).)

Volcanic eruptions on land create hot and fast pyroclastic density currents, triggering tsunamis or surges that travel over water where they reach the ocean. However, no field study has documented what happens when large volumes of erupted volcanic material are instead delivered directly into the ocean. We show how the rapid emplacement of large volumes of erupted material onto steep submerged slopes triggered extremely fast (122 kilometers per hour) and long-runout (>100 kilometers) seafloor currents. These density currents were faster than those triggered by earthquakes, floods, or storms, and they broke seafloor cables, cutting off a nation from the rest of the world. The deep scours excavated by these currents are similar to those around many submerged volcanoes, providing evidence of large eruptions at other sites worldwide.

Background and Purpose: Glucagon-like peptide-2 (GLP-2) is secreted postprandially by enteroendocrine L-cells and stimulates growth of the gut and bone. One GLP-2 analogue is approved for short bowel syndrome (SBS). To improve therapeutic efficacy, we developed biased GLP-2 receptor (GLP-2R) agonists through N-terminal modifications., Experimental Approach: Variants with Ala and Trp substitutions of the first seven positions of GLP-2(1-33) were studied in vitro for affinity, G protein activation (cAMP accumulation), recruitment of β-arrestin 1 and 2, and internalization of the human and mouse GLP-2R. The intestinotrophic actions of the most efficacious (cAMP) biased variant were examined in mice., Key Results: Ala substitutions had more profound effects than Trp substitutions. For both, alterations at positions 1, 3 and 6 most severely impaired activity. β-arrestin recruitment was more affected than cAMP accumulation. Among Ala substitutions, [H1A], [D3A] and [F6A] impaired potency (EC 50 ) for cAMP-accumulation >20-fold and efficacy (E max ) to 48%-87%, and were unable to recruit arrestins. The Trp substitutions, [A2W], [D3W] and [G4W] were partial agonists (E max of 46%-59%) with 1.7-12-fold decreased potencies in cAMP and diminished β-arrestin recruitment. The biased variants, [F6A], [F6W] and [S7W] induced less GLP-2R internalization compared with GLP-2, which induced internalization in a partly arrestin-independent manner. In mice, [S7W] enhanced gut trophic actions with increased weight of the small intestine, increased villus height and crypt depth compared with GLP-2., Conclusion and Implications: G protein-biased GLP-2R agonists with diminished receptor desensitization have superior intestinotrophic effects and may represent improved treatment of intestinal insufficiency including SBS., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: Treatment with glucagon receptor antagonists (GRAs) reduces blood glucose but causes dyslipidemia and accumulation of fat in the liver. We investigated the acute and chronic effects of glucagon on lipid metabolism in mice., Methods: Chronic effects of glucagon receptor signaling on lipid metabolism were studied using oral lipid tolerance tests (OLTTs) in overnight fasted glucagon receptor knockout (Gcgr -/- ) mice, and in C57Bl/6JRj mice treated with a glucagon receptor antibody (GCGR Ab) or a long-acting glucagon analogue (GCGA) for eight weeks. Following treatment, liver tissue was harvested for RNA-sequencing and triglyceride measurements. Acute effects were studied in C57Bl/6JRj mice treated with a GRA or GCGA 1 h or immediately before OLTTs, respectively. Direct effects of glucagon on hepatic lipolysis were studied using isolated perfused mouse liver preparations. To investigate potential effects of GCGA and GRA on gastric emptying, paracetamol was, in separate experiments, administered immediately before OLTTs., Results: Plasma triglyceride concentrations increased 2-fold in Gcgr -/- mice compared to their wild-type littermates during the OLTT (P = 0.001). Chronic treatment with GCGR Ab increased, whereas GCGA treatment decreased, plasma triglyceride concentrations during OLTTs (P < 0.05). Genes involved in lipid metabolism were upregulated upon GCGR Ab treatment while GCGA treatment had opposite effects. Acute GRA and GCGA treatment, respectively, increased (P = 0.02) and decreased (P = 0.003) plasma triglyceride concentrations during OLTTs. Glucagon stimulated hepatic lipolysis, evident by an increase in free fatty acid concentrations in the effluent from perfused mouse livers. In line with this, GCGR Ab treatment increased, while GCGA treatment decreased, liver triglyceride concentrations. The effects of glucagon appeared independent of changes in gastric emptying of paracetamol., Conclusions: Glucagon receptor signaling regulates triglyceride metabolism, both chronically and acutely, in mice. These data expand glucagon´s biological role and implicate that intact glucagon signaling is important for lipid metabolism. Glucagon agonism may have beneficial effects on hepatic and peripheral triglyceride metabolism., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Innate visually guided behaviors are thought to promote survival by guiding organisms to sources of food and safety and away from harm without requiring learning. Historically, innate behaviors have been considered hard-wired and invariable, but emerging evidence shows that many innate behaviors are flexible and complex due to modulation. Here, we investigate the modulation of the innate preference for light displayed by the Xenopus laevis tadpole, an exceptionally invasive and well-studied organism that is known to display several different innate visually guided behaviors. We found that tadpoles display a circadian-regulated oscillation in their preference for light over dark which can be altered by experimentally increasing or decreasing levels of serotonin transmission. We also found that endogenous levels of serotonin transmission during the day maintain a consistently moderate preference for light. Theoretically, a moderate preference for light, as opposed to a strong preference, optimizes survival by rendering tadpoles' behavior less predictable., Competing Interests: The authors have no competing interests., (© 2022 The Author(s).)

The pancreatic hormone, glucagon, is known to regulate hepatic glucose production, but recent studies suggest that its regulation of hepatic amino metabolism is equally important. Here, we show that chronic glucagon receptor activation with a long-acting glucagon analog increases amino acid catabolism and ureagenesis and causes alpha cell hypoplasia in female mice. Conversely, chronic glucagon receptor inhibition with a glucagon receptor antibody decreases amino acid catabolism and ureagenesis and causes alpha cell hyperplasia and beta cell loss. These effects were associated with the transcriptional regulation of hepatic genes related to amino acid uptake and catabolism and by the non-transcriptional modulation of the rate-limiting ureagenesis enzyme, carbamoyl phosphate synthetase-1. Our results support the importance of glucagon receptor signaling for amino acid homeostasis and pancreatic islet integrity in mice and provide knowledge regarding the long-term consequences of chronic glucagon receptor agonism and antagonism., Competing Interests: Thomas Kruse and Jesper F. Lau are employed by Novo Nordisk A/S. No conflicts of interest, financial or otherwise, are declared by the remaining authors., (© 2022 The Author(s).)

Background and Purpose: The incretin hormone, gastric inhibitory peptide/glucose-dependent insulinotropic polypeptide (GIP), secreted by the enteroendocrine K-cells in the proximal intestine, may regulate lipid metabolism and adiposity, but its exact role in these processes is unclear., Experimental Approach: We characterized in vitro and in vivo antagonistic properties of a novel GIP analogue, mGIPAnt-1. We further assessed the in vivo pharmacokinetic profile of this antagonist, as well as its ability to affect high-fat diet (HFD)-induced body weight gain in ovariectomised mice during an 8-week treatment period., Key Results: mGIPAnt-1 showed competitive antagonistic properties to the GIP receptor in vitro as it inhibited GIP-induced cAMP accumulation in COS-7 cells. Furthermore, mGIPAnt-1 was capable of inhibiting GIP-induced glucoregulatory and insulinotropic effects in vivo and has a favourable pharmacokinetic profile with a half-life of 7.2 h in C57Bl6 female mice. Finally, sub-chronic treatment with mGIPAnt-1 in ovariectomised HFD mice resulted in a reduction of body weight and fat mass., Conclusion and Implications: mGIPAnt-1 successfully inhibited acute GIP-induced effects in vitro and in vivo and sub-chronically induces resistance to HFD-induced weight gain in ovariectomised mice. Our results support the development of GIP antagonists for the therapy of obesity., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)