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Objective: Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass., Methods: We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation., Results: Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved., Conclusion: Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat., Competing Interests: Declaration of competing interest TMMT is a consultant and shareholder in Zihipp/Metsera. JSM and SRB are employees and shareholders in Zihipp/Metsera, which is developing gut hormone analogues for treatment of metabolic disease., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objectives: Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice., Methods: Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice., Results: Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance., Conclusions: Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TM-MT, JM and SRB declare that they are shareholders in and consultants for Zihipp Ltd., an Imperial College spin-out company that develops gut hormone analogues for the treatment of obesity and associated metabolic disorders., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Photoautotrophic marine ecosystems can lock up organic carbon in their biomass and the associated organic sediments they trap over millennia and are thus regarded as blue carbon ecosystems. Because of the ability of marine ecosystems to lock up organic carbon for millennia, blue carbon is receiving much attention within the United Nations' 2030 Agenda for Sustainable Development as a nature-based solution (NBS) to climate change, but classically still focuses on seagrass meadows, mangrove forests, and tidal marshes. However, other coastal ecosystems could also be important for blue carbon storage, but remain largely neglected in both carbon cycling budgets and NBS strategic planning. Using a meta-analysis of 253 research publications, we identify other coastal ecosystems-including mud flats, fjords, coralline algal (rhodolith) beds, and some components or coral reef systems-with a strong capacity to act as blue carbon sinks in certain situations. Features that promote blue carbon burial within these 'non-classical' blue carbon ecosystems included: (1) balancing of carbon release by calcification via carbon uptake at the individual and ecosystem levels; (2) high rates of allochthonous organic carbon supply because of high particle trapping capacity; (3) high rates of carbon preservation and low remineralization rates; and (4) location in depositional environments. Some of these features are context-dependent, meaning that these ecosystems were blue carbon sinks in some locations, but not others. Therefore, we provide a universal framework that can evaluate the likelihood of a given ecosystem to behave as a blue carbon sink for a given context. Overall, this paper seeks to encourage consideration of non-classical blue carbon ecosystems within NBS strategies, allowing more complete blue carbon accounting., (© 2024 John Wiley & Sons Ltd.)

We describe a method for defining dynamical black hole entropy in gravitational effective field theories. The entropy is constructed order by order in derivatives. For any fixed number of derivatives, the entropy satisfies a nonperturbative second law of black hole mechanics if the black hole remains within the regime of validity of effective field theories. In equilibrium the entropy reduces to the Wald entropy. It reduces to the entropy defined by Hollands et al. in theories of vacuum gravity with up to ten derivatives.

Aims: To determine whether a continuous infusion of a glucagon-like peptide receptor (GLP-1R)/glucagon receptor (GCGR) co-agonist, G3215 is safe and well tolerated in adults with overweight or obesity., Methods: A phase 1 randomized, double blind, placebo-controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes., Results: Twenty-six participants were recruited and randomized with 23 completing a 14-day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real-time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least-squares mean body weight loss of 2.39 kg was achieved with a 14-day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215-treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period., Conclusion: An adaptive continuous infusion of the GLP-1/GCGR co-agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response-directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP-1R and multi-agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Nutritional requirements of individuals vary across the lifecycle, according to activity, age and gender. To optimize human health, consideration of nutritional priorities at each stage is needed. This conference brought together multidisciplinary experts in maternal and child nutrition and health, cardiometabolic and plant-based nutrition and dietitians involved in the care of vulnerable populations, plus nutritional metabolism, health and ageing. The presentations highlighted the most important nutrition research in these areas, updating knowledge and suggesting how dietary advice and policy could be adapted to incorporate research findings. With the global increase in non-communicable disease (NCD) and nutrition being considered as a key modifiable risk factor for the prevention and management of NCD, this conference was much needed.

Aim: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios., Materials and Methods: New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays., Results: First, we show that very substantial reductions in β-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics., Conclusions: Completely abolishing β-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)