Incretin-based treatments, such as glucagon-like peptide-1 receptor (GLP-1R) agonists (eg liraglutide and semaglutide), have rapidly transformed obesity treatment. The well-documented weight loss effect from these agents is considered to be primarily a result of their actions on food intake, but frequent anecdotal reports from varied sources have suggested that they might also broadly affect consummatory behavior, including alcohol and drugs of abuse, suggesting a potential modulatory effect on reward behavior. Herein, we critically review the extant literature on the behavioral effects of GLP-1R agonists in humans, including their impact on feeding behavior, alcohol/drug intake, and overall reward response. We also consider the physiological and neurobiological underpinnings of GLP-1 actions, with a focus on its distinct central and peripheral roles, as well as its relationships with the broader energy homeostasis network. We conclude with a discussion on the implications of this line of research on how behavior is conceptualized, and the potential future directions for research.

The potential influence of the timing of eating on body weight regulation in humans has attracted substantial research interest. This review aims to critically evaluate the evidence on timed eating for weight loss, considering energetic and behavioural components to the timing of eating in humans. It has been hypothesised that timed eating interventions may alter energy balance in favour of weight loss by enhancing energy expenditure, specifically the thermic effect of food. This energetic effect has been suggested to explain greater weight loss which has been observed with certain timed eating interventions, despite comparable self-reported energy intakes to control diets. However, timed eating interventions have little impact on total daily energy expenditure, and the apparent effect of time of day on the thermic effect of food largely represents an artefact of measurement methods that fail to account for underlying circadian variation in resting metabolic rate. Differences in weight loss observed in free-living interventions are more likely explainable by real differences in energy intake, notwithstanding similar self-reported energy intakes. In addition, the energetic focus tends to overlook the role of behavioural factors influencing the timing of eating, such as appetite regulation chronotype-environment interactions, which may influence energy intake under free-living conditions. Overall, there is scant evidence that timed eating interventions are superior to general energy restriction for weight loss in humans. However, the role of behavioural factors in influencing energy intake may be relevant for adherence to energy-restricted diets, and this aspect remains understudied in human intervention trials.

Metabolic dysfunction has been long associated with severe mental illness (SMI), often viewed as a comorbidity to be managed. However, emerging evidence suggests that metabolic dysfunction, particularly at the mitochondrial level, may be a foundational element in the pathophysiology of neuropsychiatric disorders. This commentary expands on the current understanding by exploring the brain energy theory of mental illness, which posits that mitochondrial dysfunction is central to both metabolic and psychiatric conditions. The roles of insulin resistance, chronic stress and environmental factors are highlighted as shared biopsychosocial determinants that contribute to deterioration in both metabolic and mental health. The therapeutic potential of the ketogenic diet is discussed, particularly its ability to improve mitochondrial function and alleviate psychiatric symptoms. This shift in perspective, from viewing metabolic dysfunction as a secondary concern to recognising it as a root cause of SMI, has significant implications for clinical practice and research. By focusing on bioenergetic deficits and mitochondrial health, psychiatry may advance towards more effective, integrated treatment approaches that target the underlying cellular dysfunctions driving both metabolic and mental illnesses.

Obesity is a chronic, complex and multi-factorial condition with an increasing prevalence worldwide. Irregular eating schedules might be a contributing factor to these numbers through the dysregulation of the circadian system. Time-restricted eating (TRE), an approach that limits eating windows, has been studied as a strategy to treat obesity, aligning eating occasions with metabolic circadian rhythms. This review aims to provide an overview of the impact of TRE protocols on metabolic, inflammatory, oxidative stress and circadian rhythm biomarkers in people with overweight or obesity. Most studies report significant weight loss following TRE protocols. While glucose levels decreased in nearly all TRE interventions, only a few studies demonstrated statistically significant differences when compared to the control groups. The findings for c-reactive protein and TNF-α were inconsistent, with limited significant differences. Changes in lipid profile changes were variable and generally did not reach statistical significance. Both 4-hour and 6-hour TRE interventions significantly reduced 8-isoprostane levels. Additionally, TRE significantly altered clock gene expression, as well as that of genes associated with metabolic regulation in subcutaneous adipose tissue. While the evidence is still inconsistent, limiting eating to a consistent daily window of 8 to 12 h can improve insulin sensitivity, reduce blood glucose, cholesterol and triglyceride levels and promote weight loss. These effects are likely attributable to both direct metabolic impacts and indirect benefits from weight loss and improved dietary habits. However, data on circadian, inflammatory and specific metabolic biomarkers remain scarce and occasionally contradictory, highlighting the need for further research on these interventions.

Plasma levels of branched-chain amino acids (BCAA) and their metabolites, branched-chain ketoacids (BCKA), are increased in insulin resistance. We previously showed that ketoisocaproic acid (KIC) suppressed insulin-stimulated glucose transport in L6 myotubes, especially in myotubes depleted of branched-chain ketoacid dehydrogenase (BCKD), the enzyme that decarboxylates BCKA. This suggests that upregulating BCKD activity might improve insulin sensitivity. We hypothesised that increasing BCAA catabolism would upregulate insulin-stimulated glucose transport and attenuate insulin resistance induced by BCKA. L6 myotubes were either depleted of BCKD kinase (BDK), the enzyme that inhibits BCKD activity, or treated with BT2, a BDK inhibitor. Myotubes were then treated with KIC (200 μM), leucine (150 μM), BCKA (200 μM), or BCAA (400 μM) and then treated with or without insulin (100 nM). BDK depletion/inhibition rescued the suppression of insulin-stimulated glucose transport by KIC/BCKA. This was consistent with the attenuation of IRS-1 (Ser612) and S6K1 (Thr389) phosphorylation but there was no effect on Akt (Ser473) phosphorylation. The effect of leucine or BCAA on these measures was not as pronounced and BT2 did not influence the effect. Induction of the mTORC1/IRS-1 (Ser612) axis abolished the attenuating effect of BT2 treatment on glucose transport in cells treated with KIC. Surprisingly, rapamycin co-treatment with BT2 and KIC further reduced glucose transport. Our data suggests that the suppression of insulin-stimulated glucose transport by KIC/BCKA in muscle is mediated by mTORC1/S6K1 signalling. This was attenuated by upregulating BCAA catabolic flux. Thus, interventions targeting BCAA metabolism may provide benefits against insulin resistance and its sequelae.

To improve the interpretation and utilisation of blood lipids, ketones and acylcarnitine concentrations as biomarkers in clinical assessments, more information is needed on their dynamic alterations in response to dietary intake and fasting. The aim of this intervention study was to characterise the changes in serum lipid, ketone and acylcarnitine concentrations 24 h after a standardised breakfast meal. Thirty-four healthy subjects (eighteen males and sixteen females) aged 20–30 years were served a breakfast meal (∼500 kcal, 36 E% fat, 46 E% carbohydrates, 16 E% protein, 2E% fibre), after which they consumed only water for 24 h. Blood samples were drawn before and at thirteen standardised timepoints after the meal. Metabolite concentrations were plotted as a function of time since the completion of the breakfast meal. Results demonstrated that concentrations of HDL-cholesterol and LDL-cholesterol decreased until ∼2 h (–4 % for both), while TAG concentrations peaked at 3 h (+27 %). Acetoacetate and β-hydroxybutyrate were highest 24 h after the meal (+433 and +633 %, respectively). Acetylcarnitine, butyrylcarnitine, hexanoylcarnitine, octanoylcarnitine, decanoylcarnitine and dodecanoylcarnitine reached the lowest values at 60 min (decreases ranging from –47 to –70 %), before increasing and peaking at 24 h after the meal (increases ranging from +86 to +120 %). Our findings suggest that distinguishing between fasting and non-fasting blood samples falls short of capturing the dynamics in lipid, ketone, carnitine and acylcarnitine concentrations. To enhance the utility of serum acylcarnitine analyses, we strongly recommend accounting for the specific time since the last meal at the time of blood sampling.

Deficiency of vitamin B12 (B12 or cobalamin), an essential water-soluble vitamin, leads to neurological damage, which can be irreversible and anaemia, and is sometimes associated with chronic disorders such as osteoporosis and cardiovascular diseases. Clinical tests to detect B12 deficiency lack specificity and sensitivity. Delays in detecting B12 deficiency pose a major threat because the progressive decline in organ functions may go unnoticed until the damage is advanced or irreversible. Here, using targeted unbiased metabolomic profiling in the sera of subjects with low B12 levels v control individuals, we set out to identify biomarker(s) of B12 insufficiency. Metabolomic profiling identified seventy-seven metabolites, and partial least squares discriminant analysis and hierarchical clustering analysis showed a differential abundance of taurine, xanthine, hypoxanthine, chenodeoxycholic acid, neopterin and glycocholic acid in subjects with low B12 levels. Random forest multivariate analysis identified a taurine/chenodeoxycholic acid ratio, with an AUC score of 1, to be the best biomarker to predict low B12 levels. Mechanistic studies using a mouse model of B12 deficiency showed that B12 deficiency reshaped the transcriptomic and metabolomic landscape of the cell, identifying a downregulation of methionine, taurine, urea cycle and nucleotide metabolism and an upregulation of Krebs cycle. Thus, we propose taurine/chenodeoxycholic acid ratio in serum as a potential biomarker of low B12 levels in humans and elucidate using a mouse model of cellular metabolic pathways regulated by B12 deficiency.

Sucrose yield in sugarcane is a complex process regulated by both environmental and endogenous factors. However, the metabolic balance driving vegetative growth and sucrose accumulation remains poorly understood. Herein, we carried out a comprehensive assessment of carbohydrate dynamics throughout the crop cycle in two sugarcane varieties varying in biomass production, evaluating the carbon metabolism in both leaves and stalks. Our data revealed that the decline in photosynthetic rates during sugarcane maturation is associated not only to accumulation of sugars in leaves but also due to stomatal and non-stomatal limitations. We found that metabolic processes in leaves and stalks were intrinsically linked. While IACSP94-2094 had higher stalk sucrose concentration than IACSP95-5000, this latter produced more biomass. Compared to IACSP95-5000, IACSP94-2094 showed higher sucrose phosphate synthase (SPS) activity in leaves and stalks, along with lower soluble acid invertase (SAI) activity in leaves during the maximum growth stage. Interestingly, IACSP94-2094 also exhibited higher stalk SPS activity and lower stalk SAI activity than IACSP95-5000 during maturation. High biomass production by IACSP95-5000 was associated with higher sucrose synthase (SuSy) and SAI activity in leaves and higher SuSy and soluble neutral invertase (SNI) activity in stalks when compared to IACSP94-2094 during the maximum growth. Despite the contrasting strategies, both varieties displayed similar total sucrose yield, a balance between sucrose concentration and biomass production. This phenomenon implies the presence of a compensatory mechanism in sugarcane, with high biomass production compensating low sucrose accumulation and vice versa.

Circadian clocks play a key role in metabolic homeostasis, and disruption of circadian rhythms is inextricably intertwined with metabolic disorders [1]. Emerging evidence in the literature suggests that polyphenols possess the potential to modulate metabolic processes associated with circadian rhythms. This review aims to evaluate the effects of polyphenols on metabolic homeostasis via circadian rhythms and their potential mechanism(s) of action on circadian rhythmicity of clock components and linked metabolic processes, by critically assessing the literature on mammalian cells in vitro. To ensure that all relevant studies in this area were included, a systematic search protocol was developed by defining the inclusion and exclusion criteria based on the population, intervention, comparator and outcome framework, along with limiting the source of evidence to original research written in English. Three databases (Ovid Medline, Web of Science, and Scopus) were searched with no time constraints. The search identified 5842 studies and, after duplicate removal and initial screening, 48 studies were reviewed in full. Of those, 38 were eligible for inclusion. The included studies were published between 2008-2023, with a notable surge in publications after 2016, which is indicative of the growing attention towards polyphenols and circadian biology. 33 polyphenols were examined for their effects on circadian cellular processes (n = 16 papers), expression of clock genes and/or proteins (n = 26), or circadian rhythm features of clock genes (n = 10). A handful of studies examined the role of polyphenols in regulating disrupted glucose and lipid metabolism through clock components. The findings suggested that the underlying mechanisms were BMAL1-dependent. It must be noted that the effects of the reported polyphenols were elucidated at concentrations exceeding the normal range found in human plasma and target tissues (˃ 10 μM). However, a single study revealed that (−)-epigallocatechin-3-gallate (EGCG) at a physiologically-relevant concentration (10 μM), improved hepatic glucose metabolism [2]. Further, the polyphenols reported in this review exhibited the potential to influence numerous clock components, mainly BMAL1, PER2 and RORα/γ, at mRNA and/or protein levels when administered at physiologically-relevant concentrations. These polyphenols include nobiletin, tangeretin, curcumin, bavachalcone, cinnamic acid, (−)-epigallocatechin-3-gallate, resveratrol and Urolithin A. Polyphenols have the potential to regulate circadian oscillators and associated metabolic processes in various types of cells. However, there is significant methodological heterogeneity among the studies, which makes it difficult to compare outcomes. Thus, this review will help future research in the field of circadian impacts of polyphenols to integrate standardised approaches, in aspects such as utilisation of a synchronisation method and physiologically-relevant concentrations of polyphenols (≤ 10 μM) in cultured cells. This is critical for understanding how polyphenols might modulate circadian-metabolic health in humans.

PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery of the millennium, as it was identified in 1999. Although PARP2 was described initially as a DNA repair factor, it is now evident that PARP2 partakes in the regulation or execution of multiple biological processes as inflammation, carcinogenesis and cancer progression, metabolism or oxidative stress-related diseases. Hereby, we review the involvement of PARP2 in these processes with the aim of understanding which processes are specific for PARP2, but not for other members of the ART family. A better understanding of the specific functions of PARP2 in all of these biological processes is crucial for the development of new PARP-centred selective therapies.

Osteoarthritis (OA) commonly affects the knee and hip joints and accounts for 19.3% of disability-adjusted life years and years lived with disability worldwide (Refs 1, 2). Early management is important in order to avoid disability uphold quality of life (Ref. 3). However, a lack of awareness of subclinical and early symptomatic stages of OA often hampers early management (Ref. 4). Moreover, late diagnosis of OA among those with severe disease, at a stage when OA management becomes more complicated is common (Refs 5, 6, 7, 8). Established risk factors for the development and progression of OA include increasing age, female, history of trauma and obesity (Ref. 9). Recent studies have also drawn a link between OA and metabolic syndrome, which is characterized by insulin resistance, dyslipidaemia and hypertension (Refs 10, 11).

Quinclorac controls crabgrass (Digitaria spp.) in cool- and warm-season turfgrass species. Herbicide-resistant smooth crabgrass [Digitaria ischaemum (Schreb.) Schreb. ex Muhl.] biotypes have evolved due to recurrent usage of quinclorac. Two Mississippi populations (MSU1 and MSU2) of D. ischaemum were characterized using standard greenhouse dose–response screens to assess their resistance relative to known susceptible populations. Subsequent investigations explored mechanisms of resistance, including examining cyanide accumulation, glutathione S-transferase (GST) activity, and the potential involvement of cytochrome P450s in MSU1, MSU2, and a susceptible (SMT2). Resistant populations MSU1 and MSU2 required 80 and 5 times more quinclorac, respectively, to reach 50% biomass reduction than susceptible populations. The SMT2 biotype accumulated three times more cyanide than the resistant MSU1 and MSU2 populations. GST activity was elevated in resistant MSU1 and MSU2 populations. Furthermore, quinclorac concentrations in treated resistant populations were elevated when plants were pretreated with the P450 inhibitor malathion. These findings suggest a non–target site based mechanism of resistance involving the accumulation of cyanide. This may provide a scientific basis for understanding the occurrence of quinclorac-resistant D. ischaemum, although further research is needed to investigate potential target-site mechanisms of resistance.

The evolution of herbicide resistance in weeds can reduce the herbicide’s efficacy, depleting crop yield and quality. Our group previously confirmed 2,4-D resistance in three Palmer amaranth (Amaranthus palmeri S. Watson) populations (R1 to R3). In the current study, the first filial (F1) seeds of 2,4-D–resistant populations were subjected to screening tests for resistance to other auxin-mimicking herbicides, florpyrauxifen-benzyl (FPB; 30 g ai ha−1) and dicamba (560 g ae ha−1). Dicamba killed all resistant populations. FPB provided 100% control of only the R3 population. Sensitivities to FPB were reduced by 2 and 35 percentage points in R1 and R2 populations, respectively. Pretreatment with malathion increased FPB sensitivity by 15 percentage points in the R2 population. FPB resistance characterization and mechanism were evaluated using a purified line of the R2 population (F2). The FPB sensitivity was 29-fold lower in the F2 line than in the susceptible (S) standard. Absorption, translocation, and total metabolism of FPB were similar for S and R2 populations. However, less florpyrauxifen-acid (FPA) was detected in the R2 population (17.0% to 25.4%) than in the S population (22.8% to 33.2%), due to its rapid metabolism and/or reduced production with resistance evolution. Because the results of the non–target site resistance mechanism evaluation observed in this study were insufficient to account for the 29-fold reduced sensitivity of the R2 population to FPB, further genetic studies are needed to investigate the presence of target-site resistance in that population.