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Type 2 diabetes (T2D), which has currently become a global pandemic, is a metabolic disease largely characterised by impaired insulin secretion and action. Significant progress has been made in understanding T2D aetiology and pathogenesis, which is discussed in this review. Extrapancreatic pathology is also summarised, which demonstrates the highly multifactorial nature of T2D. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells during the postprandial period. Given that native GLP-1 has a very short half-life, GLP-1 mimetics with a much longer half-life have been developed, which are currently an effective treatment option for T2D by enhancing insulin secretion in patients. Interestingly, there is continual emerging evidence that these therapies alleviate some of the post-diagnosis complications of T2D. Additionally, these therapies have been shown to induce weight loss in patients, suggesting they could be an alternative to bariatric surgery, a procedure associated with numerous complications. Current GLP-1-based therapies all act as orthosteric agonists for the GLP-1 receptor (GLP-1R). Interestingly, it has emerged that GLP-1R also has allosteric binding sites and agonists have been developed for these sites to test their therapeutic potential. Recent studies have also demonstrated the potential of bi- and tri-agonists, which target multiple hormonal receptors including GLP-1R, to more effectively treat T2D. Improved understanding of T2D aetiology/pathogenesis, coupled with the further elucidation of both GLP-1 activity/targets and GLP-1R mechanisms of activation via different agonists, will likely provide better insight into the therapeutic potential of GLP-1-based therapies to treat T2D.

A number of hypotheses about compensatory mechanisms that allow ectothermic animals to cope with the latitudinal decrease in ambient temperature (TA) have been proposed during the last century. One of these hypotheses, the ‘metabolic homeostasis’ hypothesis (MHH), states that species should show the highest thermal sensitivity of the metabolic rate (Q10-SMR) at the colder end of the range of TAs they usually experience in nature. This way, species should be able to minimize maintenance costs during the colder hours of the day, but quickly take advantage of increases in TA during the warmer parts of the day. Here, we created a dataset that includes Q10-SMR values for 58 amphibian species, assessed at four thermal ranges, to evaluate three predictions derived from the MHH. In line with this hypothesis, we found that: (i) Q10-SMR values tended to be positively correlated with latitude when measured at lower TAs, but negative correlated with latitude when measured at higher TAs, (ii) Q10-SMR measured at lower TAs were higher in temperate species, whereas Q10-SMR measured at higher TAs were higher in tropical species, and (iii) the experimental TA at which Q10-SMR was maximal for each species decreased with latitude. This is the first study to our knowledge showing that the relationship between Q10-SMR and latitude in ectotherms changes with the TA at which Q10-SMR is assessed, as predicted from an adaptive hypothesis. This article is part of the theme issue ‘Physiological diversity, biodiversity patterns and global climate change: testing key hypotheses involving temperature and oxygen’.

Human immunodeficiency virus (HIV) infection remains a global public health problem that affects thousands of people annually. One of the main comorbidities identified in HIV-positive patients undergoing antiretroviral treatment is insufficiency of vitamin D, a key hormone involved in physiological and metabolic processes in the human body. This review aimed to evaluate the importance of vitamin D3 supplementation in HIV-positive patients with serum concentrations below the recommended limits. The literature search included indexed articles published from 2015 to 2023. The article search strategy included the databases of the National Library of Medicine (PUBMED) and Scientific Electronic Library Online (SCIELO). Non-acquired immunodeficiency syndrome (AIDS)-related opportunistic pathologies are the main causes of morbidity and mortality despite the efficacy of antiretroviral therapy. Several studies have shown that hypovitaminosis D is diagnosed during HIV progression and may be associated with reduced survival rates, highlighting the importance of measuring vitamin D serum levels and providing exogenous vitamin D3 supplementationif needed for these patients. Several studies have pointed out the benefits of vitamin D3 supplementation in HIV-infected patients, independent of antiretroviral treatment, such as the reduction of inflammatory processes and mediators related to bone renewal, increase in CD4 + T lymphocyte count, and increase in antibacterial response against invading microorganisms. Given the importance of this disease worldwide, which is associated with a high number of deaths, there is justification for intensifying and deepening research on the potential and significant role of vitamin D3 supplementation.

Abstract Sensing and responding to changes in nutrient levels, including those of glucose, lipids, and amino acids, by the body is necessary for survival. Accordingly, perturbations in nutrient sensing are tightly linked with human pathologies, particularly metabolic diseases such as obesity, type 2 diabetes mellitus, and other complications of metabolic syndromes. The conventional view is that amino acids are fundamental elements for protein and peptide synthesis, while recent studies have revealed that amino acids are also important bioactive molecules that play key roles in signaling pathways and metabolic regulation. Different pathways that sense intracellular and extracellular levels of amino acids are integrated and coordinated at the organismal level, and, together, these pathways maintain whole metabolic homeostasis. In this review, we discuss the studies describing how important sensing signals respond to amino acid availability and how these sensing mechanisms modulate metabolic processes, including energy, glucose, and lipid metabolism. We further discuss whether dysregulation of amino acid sensing signals can be targeted to promote metabolic disorders, and discuss how to translate these mechanisms to treat human diseases. This review will help to enhance our overall understanding of the correlation between amino acid sensing and metabolic homeostasis, which have important implications for human health. Graphical Abstract Graphical Abstract

Chlorogenic acid (CGA) is a type of polyphenol compound found in rich concentrations in many plants such as green coffee beans. As an active natural substance, CGA exerts diverse therapeutic effects in response to a variety of pathological challenges, particularly conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional functions, including neuroprotection for neurodegenerative disorders and diabetic peripheral neuropathy, anti-inflammation, anti-oxidation, anti-pathogens, mitigation of cardiovascular disorders, skin diseases, diabetes mellitus, liver and kidney injuries, and anti-tumor activities. Mechanistically, its integrative functions act through the modulation of anti-inflammation/oxidation and metabolic homeostasis. It can thwart inflammatory constituents at multiple levels such as curtailing NF-kB pathways to neutralize primitive inflammatory factors, hindering inflammatory propagation, and alleviating inflammation-related tissue injury. It concurrently raises pivotal antioxidants by activating the Nrf2 pathway, thus scavenging excessive cellular free radicals. It elevates AMPK pathways for the maintenance and restoration of metabolic homeostasis of glucose and lipids. Additionally, CGA shows functions of neuromodulation by targeting neuroreceptors and ion channels. In this review, we systematically recapitulate CGA’s pharmacological activities, medicinal properties, and mechanistic actions as a potential therapeutic agent. Further studies for defining its specific targeting molecules, improving its bioavailability, and validating its clinical efficacy are required to corroborate the therapeutic effects of CGA.

Traditionally, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a 91 kDa transcription factor, regulates lipid metabolism and long-chain fatty acid oxidation by upregulating the expression of several genes of the tricarboxylic acid cycle and the mitochondrial fatty acid oxidation pathway. In addition, PGC-1α regulates the expression of mitochondrial genes to control mitochondria DNA replication and cellular oxidative metabolism. Recently, new insights showed that several myokines such as irisin and myostatin are epigenetically regulated by PGC-1α in skeletal muscles, thereby modulating systemic energy balance, with marked expansion of mitochondrial volume density and oxidative capacity in healthy or diseased myocardia. In addition, in our studies evaluating whether PGC-1α overexpression in epicardial adipose tissue can act as a paracrine organ to improve or repair cardiac function, we found that overexpression of hepatic PGC-1α increased hepatic fatty acid oxidation and decreased triacylglycerol storage and secretion in vivo and in vitro. In this review, we discuss recent studies showing that PGC-1α may regulate mitochondrial fusion–fission homeostasis and affect the renal function in acute or chronic kidney injury. Furthermore, PGC-1α is an emerging protein with a biphasic role in cancer, acting both as a tumor suppressor and a tumor promoter and thus representing a new and unresolved topic for cancer biology studies. In summary, this review paper demonstrates that PGC-1α plays a central role in coordinating the gene expression of key components of mitochondrial biogenesis and as a critical metabolic regulator in many vital organs, including white and brown adipose tissue, skeletal muscle, heart, liver, and kidney.

Physical activity exerts multiple beneficial effects and the myokine concept provides a framework for understanding the molecular pathways that integrate contracting muscle in the complex network of organ communication. This network includes multiple distinct and distal organs; however, the autocrine and paracrine effects of myokines within skeletal muscle (in which they are produced) also need specific attention. In humans, the functional allocation of myokines remains limited and recent findings on fibre type-specific myokine signatures point to an additional level of complexity. Myokines are involved in the anti-inflammatory effect of physical activity and, therefore, critically counteract insulin resistance and the metabolic perturbations of obesity and type 2 diabetes. Future work needs to address the role of myokines in concert with other crosstalk molecules, and to define their specific impact for metabolic homeostasis.

Adipose tissue (AT) is a highly heterogeneous and dynamic organ that plays important roles in regulating energy metabolism and insulin sensitivity. In addition to its classical roles in nutrient sensing and energy storage/dissipation, AT secretes a large number of bioactive molecules (termed adipokines) participating in immune responses and metabolic regulation through their paracrine and/or endocrine actions. Adipose-derived extracellular vesicles (ADEVs), including exosomes, microvesicles (MVs), and apoptotic bodies, have recently emerged as a novel class of signal messengers, mediating intercellular communications and inter-organ crosstalk. In AT, ADEVs derived from adipocytes, immune cells, mesenchymal stem cells, endothelial cells are actively involved in modulation of immune microenvironment, adipogenesis, browing of white adipose tissue, adipokine release and tissue remodeling. Furthermore, ADEVs exert their metabolic actions in distal organs (such as liver, skeletal muscle, pancreas and brain) by sending genetic information (mainly in the form of microRNAs) to their target cells for regulation of gene expression. Here, we provide an updated summary on the nature and composition of ADEVs, and their pathophysiological functions in regulating immune responses, whole-body insulin sensitivity and metabolism. Furthermore, we highlight the latest clinical evidence supporting aberrant production and/or function of ADEVs as a contributor to obesity-related chronic inflammation and metabolic complications and discuss the opportunities and challenges in developing novel therapies by targeting ADEVs.

Adipose tissue (AT), composed mainly of adipocytes, plays a critical role in lipid control, metabolism, and energy storage. Once considered metabolically inert, AT is now recognized as a dynamic endocrine organ that regulates food intake, energy homeostasis, insulin sensitivity, thermoregulation, and immune responses. This review examines the multifaceted role of adiponectin, a predominant adipokine released by AT, in glucose and fatty acid metabolism. We explore the regulatory mechanisms of adiponectin, its physiological effects and its potential as a therapeutic target for metabolic diseases such as type 2 diabetes, cardiovascular disease and fatty liver disease. Furthermore, we analyze the impact of various dietary patterns, specific nutrients, and physical activities on adiponectin levels, highlighting strategies to improve metabolic health. Our comprehensive review provides insights into the critical functions of adiponectin and its importance in maintaining systemic metabolic homeostasis.

Summary Submergence limits plants' access to oxygen and light, causing massive changes in metabolism; after submergence, plants experience additional stresses, including reoxygenation, dehydration, photoinhibition and accelerated senescence. Plant responses to waterlogging and partial or complete submergence have been well studied, but our understanding of plant responses during post‐submergence recovery remains limited. During post‐submergence recovery, whether a plant can repair the damage caused by submergence and reoxygenation and re‐activate key processes to continue to grow, determines whether the plant survives. Here, we summarize the challenges plants face when recovering from submergence, primarily focusing on studies of Arabidopsis thaliana and rice (Oryza sativa). We also highlight recent progress in elucidating the interplay among various regulatory pathways, compare post‐hypoxia reoxygenation between plants and animals and provide new perspectives for future studies.