Mental illnesses and psychotropic drug use are associated with an increased risk of weight gain and metabolic disorders. Growing evidence suggests that agonists of the glucagon-like peptide-1 receptor (GLP-1RAs) might be safe and effective weight loss medications. However, the current evidence for the use of GLP-1RAs in individuals with obesity and mental illness is limited.

Evaluation of the safety and the impact of GLP-1RAs on mental health and psychotropics-induced metabolic disorders such as obesity and type 2 diabetes (T2D).

A literature search from January 1st, 2010 to August 31st, 2024 was conducted using PubMed and Cochrane Library online databases. Studies comprising adults with obesity or/and T2D and mental illness were included. Studies that examined individuals with obesity or/and T2D without mental illness and completed psychiatric questionnaires before and after GLP-1RAs treatment were also included.

From the 36 included studies 18 examined the weight-reducing effect of GLP-1RAs in patients with mental disorders and the other studies examined patients without mental illness. GLP-1RAs lead to a significant weight loss and improvement of glycemic control in patients with mental illness on psychotropics. They showed a beneficial effect on mental health in patients with and without mental disorders and were not associated with a worsening of mental state, suicidality, new-onset mental illness, or increased psychiatric admissions.

GLP-1RAs are safe and effective weight loss treatments for individuals with obesity and mental illness exerting a positive effect on mental state and quality of life. There is a need for RCTs with larger sample sizes, a longer treatment duration and longer follow-up periods to evaluate the long-term effect of GLP-1RAs. It would be of great interest to conduct studies investigating the use of GLP-1RAs with the purpose to treat mental illness in order to directly assess their use in improving mental health.

The gut microbiota may protect against obesity and chronic metabolic conditions by regulating the immune response to dietary triggers. Yet the specific bacteria that control the overactivation of the immune system in obesity and their mode of action remain largely unknown. Here we surveyed 7,569 human metagenomes and observed an association between the gut symbiont Phascolarctobacterium faecium and non-obese adults regardless of nationality, sex or age. In a mouse model of diet-induced obesity, we confirmed the specificity of P. faecium DSM 32890 anti-obesogenic properties compared with other species of the same genus. P. faecium reversed the inflammatory phenotype associated with obesity. Specifically, P. faecium promoted polarization of alternatively activated macrophages (M2), which reversed the obesity-induced increase in gut-resident type 1 innate lymphoid cells. This resulted in mitigation of glucose intolerance, adiposity and body weight gain irrespective of treatment with live or pasteurized bacteria. The metabolic benefits were independent of the adaptive immune system, but they were abolished by an inhibitor of M2 polarization in mice. P. faecium directly promoted M2-macrophage polarization through TLR2 signalling and these effects seemed to be independent of gut microbiota changes. Overall, we identify a previously undescribed gut commensal bacterium that could help mitigate obesity and metabolic comorbidities by retuning the innate immune response to hypercaloric diets.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has emerged as a pivotal therapeutic agent in the management of the cardio-renal-metabolic continuum. Initially developed for glycaemic control in Type 2 diabetes mellitus, its benefits extend far beyond glucose regulation. Clinical trials have demonstrated semaglutide's potential to reduce major adverse cardiovascular events, particularly in overweight/obese patients with high cardiovascular risk, as well as improving functional capacity in patients suffering from heart failure with preserved left ventricular function. Additionally, it has shown promise in improving renal outcomes, such as slowing the progression of albuminuria and reducing the risk of chronic kidney disease in diabetic populations. These effects are likely due to its multifaceted mechanisms, including anti-inflammatory properties, weight reduction, blood pressure lowering, and direct renal protection. This review synthesizes current evidence on semaglutide's role in the interrelated domains of cardiovascular, renal, and metabolic health.

Dual incretin agonists are among the most effective pharmaceutical treatments for obesity and type 2 diabetes to date. Such therapeutics can target two receptors, such as the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor in the case of tirzepatide, to improve glycemia and reduce body weight. Regarding body weight effects, GIPR signaling is thought to involve at least two relevant mechanisms: the enhancement of food intake reduction and the attenuation of aversive effects caused by GLP-1R agonists. Although it is known that dual GLP-1R-GIPR agonism produces greater weight loss than GLP-1R agonism alone, the precise mechanism is unknown.

To address this question, we used mice lacking GIPR in the whole body, GABAergic neurons, or glutamatergic neurons. These mice were given various combinations of GLP-1R and GIPR agonist drugs with subsequent food intake and conditioned taste aversion measurements.

A GIPR knockout in either the whole body or selectively in inhibitory GABAergic neurons protects against diet-induced obesity, whereas a knockout in excitatory glutamatergic neurons had a negligible effect. Furthermore, we found that GIPR in GABAergic neurons is essential for the enhanced weight loss efficacy of dual incretin agonism, yet, surprisingly, its removal enhances the effect of GLP-1R agonism alone. Finally, GIPR knockout in GABAergic neurons prevents the anti-aversive effects of GIPR agonism.

Our findings are consistent with GIPR research at large in that both enhancement and removal of GIPR signaling are metabolically beneficial. Notably, however, our findings suggest that future obesity therapies designed to modulate GIPR signaling, whether by agonism or antagonism, would be best targeted towards GABAergic neurons.

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP.

In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases.

Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)-a key GLP-1RA target-mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.

The objective of this study is to generate an algorithm for making predictions about individual treatment responses to a lifestyle intervention for weight loss to maximize treatment effectiveness and public health impact.

Using data from Action for Health in Diabetes (Look AHEAD), a national, multisite clinical trial that ran from 2001 to 2012, and machine-learning techniques, we generated predicted individual treatment effects for each participant. We tested for heterogeneity in treatment response and computed the degree to which treatment effects could be improved by targeting individuals most likely to benefit.

We found significant individual differences in effects of the Look AHEAD intervention. Based on these predictions, two-thirds of the sample was predicted to experience a treatment effect within ±2% weight loss from the average treatment effect. If the treatment was targeted to the 69% of patients expected to meet a 7% weight-loss target at 1-year follow-up, the average treatment effect increases, with 10% average observed weight loss in the intervention group.

The Look AHEAD intervention would achieve a 10% average weight reduction if targeted to those most likely to benefit. Future research must seek external validation of these predictions. We make this algorithm available with instructions for use to demonstrate its potential capacity to inform shared decision-making and patient-centered care.

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates promise as a potent medication for obesity. However, the extent to which its weight-reducing effects go beyond suppressing appetite remains unclear. This study aimed to elucidate this by establishing a pair-fed control group, effectively eliminating the influence of reduced caloric intake.

Mice fed on a chow diet or a high-fat diet received single or long-term intracerebroventricular (i.c.v.) injections of tirzepatide or vehicle. The vehicle-treated mice were pair-fed to the tirzepatide-treated group to avoid the impact induced by different caloric intakes. Body weight and food intake were monitored daily. Respiratory exchange ratio (RER) was determined in metabolic cages. Fat utilization was calculated based on RER. Parameters of lipid metabolism were evaluated.

Mice receiving i.c.v. administration of tirzepatide exhibited significant reductions in body weight and fat content compared with pair-fed controls. These effects were mediated by increased lipolytic capacity in white adipose tissue and enhanced thermogenesis in brown and beige adipose tissues, leading to decreased RER and increased lipid utilization. Mechanistic investigations revealed that these effects were primarily mediated by sympathetic nervous system innervation of adipose tissues. This innervation, in turn, might be associated with the neuronal activity changes in the dorsomedial hypothalamus and the nucleus of the solitary tract within the hindbrain.

These findings establish a critical role for tirzepatide in shifting the substrate preference to fat utilization through the central nervous system-adipose tissue axis, promoting weight loss independent of food intake.

Alcohol use disorder (AUD) is a complex psychiatric condition with limited effective treatment options. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as potential AUD treatment, as they have been shown to modulate reward-related behaviours, including those linked to alcohol consumption. However, the underlying mechanisms and neurocircuitry remain unclear. This study investigated the role of GLP-1R in the lateral septum (LS), a brain region highly expressing GLP-1R and implicated in reward-related behaviours, including alcohol-induced reward and consumption.

Behavioural, neurochemical, molecular, and electrophysiological methods were used to investigate the effect of LS GLP-1R signalling in alcohol-mediated responses in rodents.

LS GLP-1R activation attenuated alcohol's rewarding effects, reducing locomotor stimulation, place preference, and accumbal dopamine release. Intra-LS infusion of the GLP-1R agonist exendin-4 (Ex4) reduced alcohol intake dose-dependently without affecting food or water consumption, while GLP-1R inhibition increased alcohol intake. Furthermore, LS GLP-1R expression correlated with alcohol intake in male but not female rats, suggesting sex-specific effects of long-term alcohol exposure. Ex vivo electrophysiology indicated that GLP-1R activation depressed LS neurotransmission via a gamma-aminobutyric acid (GABA)A receptor-dependent mechanism.

This study provides new insights into how GLP-1R agonists may reduce alcohol intake. Overall, the findings underscore the potentially inhibitory neuromodulatory role of LS GLP-1R in regulating alcohol consumption through the modulation of dopaminergic reward processes tentatively involving GABA transmission.

Swedish Research Council (2023-2600), Sahlgrenska University HospitalLUA/ALF (grant no. 723941), Adlerbertska Research Foundation and Professor Bror Gadelius Foundation.

The global prevalence of obesity is skyrocketing at an alarming rate, with recent data estimating that one-in-eight people are now living with the disease. Obesity is a chronic metabolic disorder that shares underlying pathophysiology with other metabolically-linked diseases such as type 2 diabetes mellitus, cardiovascular disease and diabetic cardiomyopathy. There is a distinct correlation between type 2 diabetes status and the likelihood of heart failure. Of note, there is an apparent sexual dimorphism, with women disproportionately affected with respect to the degree of severity of the cardiac phenotype of diabetic cardiomyopathy that results from diabetes. The current pharmacotherapies available for the attenuation of hyperglycaemia in type 2 diabetes are not always effective, and have varying degrees of efficacy in the setting of heart failure. Insulin can worsen heart failure prognosis whereas metformin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and more recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs), have demonstrated cardioprotection with their administration. This review will highlight the advancement of incretin therapies for individuals with diabetes and heart failure and explore newly-reported evidence of the clinical usefulness of GLP-1R agonists in this distinct phenotype of heart failure.

Glucagon-like peptide-1 receptor agonists (e.g., semaglutide) potently induce weight loss, thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency.

C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rates of ATP production and oxygen (O2) consumption were measured via high-resolution respirometry and fluorometry to determine OXPHOS efficiency in muscle at these two time points.

Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O2 consumed in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (LYRM7 and TTC19; p < 0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits.

These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

In order to investigate whether a central nervous system penetrant anti-inflammatory could augment or sustain obesity treatment with semaglutide (Wegovy), a glucagon-like peptide-1 receptor (GLP-1R) agonist, we tested two hypotheses in models of diet-induced obesity (DIO): 1) a centrally penetrant NLPR3 inhibitor, NT-0796, drives enhanced weight loss when combined with low-dose semaglutide, compared to monotherapy; and 2) NT-0796 monotherapy sustains weight loss induced by semaglutide.

Mice fed a standard high-fat or a polyunsaturated fatty acid diet served as models of DIO and were dosed with low-dose semaglutide, NT-0796, or combinations. Body weight, food intake, peripheral inflammatory markers, and hypothalamic glial fibrillary acidic protein expression were assessed.

Combined dosing of NT-0796 with semaglutide drove greater weight loss than either monotherapy alone, and this effect was enhanced in mice consuming the polyunsaturated fatty acid diet. In addition, NT-0796 sharply limited weight regain following cessation of semaglutide therapy and normalized markers of both peripheral inflammation and hypothalamic astrogliosis to a far greater extent than either semaglutide or calorie restriction.

Alleviation of obesity-associated inflammation via NLRP3 inhibition 1) constitutes an effective weight-loss strategy as monotherapy in mice with DIO, 2) augments the weight-loss efficacy of a subtherapeutic dose of semaglutide, and 3) blocks recovery of lost weight following cessation of semaglutide.

Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.

Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for maximal weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR knockout (KO) mice, and the weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. Wild-type mice treated with GIPR-Ab/GLP-1 and CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodelling, lipid metabolism and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signalling are required for the full weight loss effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate.

Bariatric surgery (BS) has emerged as a crucial and effective treatment for severe obesity (SO), providing significant and sustained weight loss and improving comorbidities. Optimizing perioperative careparticularly through structured prehabilitation is crucial for improving surgical outcomes and long-term weight management. This review examines the role of prehabilitation, nutrition, psychological support, physical activity, and pharmacologic treatment in improving the effectiveness of BS.

Despite the benefits of prehabilitation, there are significant differences in the way it is implemented in different healthcare centers. Protocols vary widely in terms of duration, components and intensity, leading to inconsistencies in patient preparation and postoperative recovery. Many patients still do not receive multidisciplinary support from dietitians, psychologists or physiotherapists prior to surgery, which can affect long-term outcomes. Barriers to effective prehabilitation include a lack of standardized guidelines, insufficient healthcare resources and limited patient adherence due to lack of awareness, low motivation or logistical constraints. Despite its proven benefits, structured prehabilitation lasting at least 3-6 months is not available to all patients, as access remains unequal and suboptimal in many healthcare settings. Prehabilitation is an important but underutilized component of BS preparation. Standardizing protocols and ensuring multidisciplinary, patient-centered support are essential to maximizing surgical benefit. Overcoming barriers such as healthcare system limitations, patient motivation and knowledge gaps is critical to integrating prehabilitation into routine bariatric care. This review emphasizes the need for evidence-based, multimodal prehabilitation strategies to improve perioperative care and long-term outcomes for BS patients.

Glucagon-like peptide- 1 receptor agonists (GLP- 1 RA) are a rapidly expanding class of medications used to treat many chronic diseases. This review explores factors that may contribute to accelerated muscle loss among higher-risk patient populations and describes tailored interventions to reduce the risk of accelerated sarcopenia and frailty.

While GLP- 1 RA can result in total weight loss upwards of 25%, recent studies show that they can also lead to significant loss of lean body mass, reaching as high as 15-40% of total weight lost. This rapid and significant decline in muscle mass while taking GLP- 1 RA places certain patient populations already predisposed to sarcopenia at higher risk for muscle loss and adverse events. Currently, there is insufficient evidence delving into the impact of GLP- 1 RA on body composition among older adults, patients with chronic kidney disease, liver disease, and inflammatory bowel disease. However, research suggests that a high protein diet and resistance training may help prevent loss of muscle mass during GLP- 1 RA usage. A targeted and individualized nutrition and physical activity regimen should be instituted for each patient with a focus on optimizing protein intake and performing frequent resistance training in order to minimize loss of muscle mass while promoting the loss of fat mass. Future research should evaluate the impact of GLP- 1 RA on sarcopenia in high-risk patient populations.

Clinical data as well as animal and cell studies indicate that certain antidiabetic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), exert therapeutic effects in Alzheimer's disease (AD) by modulating amyloid-β peptide (Aβ) metabolism. Meanwhile, the direct interactions between GLP-1RAs and Aβ and their functional consequences remain unexplored. In this study, the interactions between monomeric Aβ40/Aβ42 of GLP-1(7-37) and its several analogs (semaglutide (Sema), liraglutide (Lira), exenatide (Exen)) were studied using biolayer interferometry and surface plasmon resonance spectroscopy. The quaternary structure of GLP-1RAs was investigated using dynamic light scattering. The effects of GLP-1RAs on Aβ fibrillation were assessed using the thioflavin T assay and electron microscopy. The impact of GLP-1RAs on Aβ cytotoxicity was evaluated via the MTT assay. Monomeric Aβ40 and Aβ42 directly bind to GLP-1(7-37), Sema, Lira, and Exen, with the highest affinity for Lira (the lowest estimates of equilibrium dissociation constants were 42-60 nM). GLP-1RAs are prone to oligomerization, which may affect their binding to Aβ. GLP-1(7-37) and Exen inhibit Aβ40 fibrillation, whereas Sema promotes it. GLP-1 analogs decrease Aβ cytotoxicity toward SH-SY5Y cells, while GLP-1(7-37) enhances Aβ40 cytotoxicity without affecting the cytotoxic effect of Aβ42. Overall, GLP-1RAs interact with Aβ and differentially modulate its fibrillation and cytotoxicity, suggesting the need for further studies of our observed effects in vivo.

Background: Fixed-ratio combinations (FRCs) provide an alternative to intensified conservative insulin treatments (ICTs); however, therapy simplification in patients with high total daily insulin dose (TDD) or high HbA1c is a debated issue; additionally, its influence on target organ damage (TOD) is less known. Methods: Data were retrospectively collected from patients with Type 2 diabetes, including 58 patients who continued ICT and 104 patients who underwent therapy simplification between January 1, 2017, and January 1, 2023. Patient characteristics and therapy details are at baseline and 3, 6, 12, and 24 months after FRC initiation. Results: HbA1c significantly decreased in both groups (-0.9% [-1.6%, -0.5%] with ICT vs. -1.3% [-2.1%, -0.3%] with FRC), whereas body weight significantly decreased only after simplification (-1 kg [-4, 1] vs. -5 kg [-7, -2]). Diabetes duration was not associated with therapy efficacy. Significant HbA1c reduction and FRC dose elevation occurred earlier in patients with an initial HbA1c > 8.0% than in those with an initial HbA1c < 8.0%. FRC dose was significantly higher at 3 months in patients with a TDD of > 60 U/day than in those with lower TDD. Relative risk reduction with therapy simplification was 72.1%, 50.6%, 32.3%, and 59.7% for hypoglycemia, renal function decline, microalbuminuria, and macrovascular complications, respectively. Risk of retinopathy, neuropathy, and chronic kidney disease did not significantly change with FRCs. Discussion: FRCs are safe and as effective as ICT even in patients with high initial HbA1c, high TDD, or long diabetes duration. A protective role of FRCs in diabetic ASCVD has been proven, but their protective role in CKD was not observed. Conclusions: The significant improvements in glycemic and weight control, as well as in TODs, suggest that therapy simplification may represent a more favorable approach compared to the continuation of previous ICT even in patients characterized by high baseline TDD and HbA1c levels.

Disease-modifying treatments for major neurocognitive disorders, including Alzheimer's disease, Parkinson's disease and other cognitive deficits, are among the main unmet needs in modern medicine. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently licensed for the treatment of type 2 diabetes mellitus and obesity, offer a novel, multilayered mechanism for intervention in neurodegeneration through intermediate, aetiology-agnostic pathways, likely involving metabolic, inflammatory and several other relevant neurobiological processes. In vitro and animal studies have revealed promising signals of neuroprotection, with preliminary supportive evidence emerging from recent pharmacoepidemiological investigations and clinical trials. In this article, we comprehensively review studies that investigate the impact of GLP-1RAs on the various aetiologies of cognitive impairment and dementia syndromes. Focusing on evidence from human studies, we highlight how brain energy homeostasis, neurogenesis, synaptic functioning, neuroinflammation and other cellular stress responses, pathological protein aggregates, proteostasis, cerebrovascular system and blood-brain barrier dynamics may underlie GLP-1RA putative neuroprotective effects. We then report and appraise evidence from clinical studies, including observational investigations, clinical trials and pooled analyses. Finally, we discuss current challenges and perspectives ahead for research and clinical implementation of GLP-1RAs for the care of people with major neurocognitive disorders, including their individual brain penetrance potential, the need for response biomarkers and disease stage-based indications, their possible non-specific effects on brain health, their profile in terms of adverse events and other unwanted effects, the lack of long-term data for efficacy and safety, and issues surrounding cost and availability of treatment.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that modulates glucose metabolism and insulin secretion. Recent translational and clinical research has evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs), a class of drugs that mimic the action of native GLP-1 in the central nervous system (CNS). In addition to the efficacy of GLP-1 for the treatment of diabetes mellitus and obesity, preliminary evidence indicates GLP-1s have neuroprotective, therapeutic, and disease modification effects for select neurodegenerative disorders (e.g. Parkinson's disease, Alzheimer's disease). Among the available GLP-1 RAs, relatively few have been shown to be CNS penetrant. This article synthesizes extant literature reporting on CNS penetrants of GLP-1 RAs as proxied by brain imaging studies. Where available, studies that reported on the bioavailability of GLP-1 RAs in the CNS were identified.

A comprehensive search of PubMed, Ovid, and Web of Science from database inception to July 2024 was conducted. Inclusion criteria were English language publications with no date restrictions, preclinical and clinical studies with participants aged 18-80 and studies which focused on GLP-1 RAs including: "Semaglutide" or "Ozempic" or "Rybelsus" or "Wegovy" or "Dulaglutide" or "Trulicity" or "Exenatide" or "Byetta" or "Bydureon" or "Liraglutide" or "Lixisenatide" or "Tirzepatide" or "Mounjaro" or "Zepbound" or "Bydureon BCise" or "Adlyxin" or "Victoza" or "Saxenda".

We identified 14 studies that were included in this synthesis. Preclinical studies suggest that select GLP-1 RAs cross the blood-brain barrier (BBB) (i.e. liraglutide, semaglutide, and exenatide). Replicated evidence suggests that CNS penetration of GLP-1 RAs can be proxied by reported effects of GLP-1 RAs on brain connectivity in human participants.

 Preclinical studies indicate that select GLP-1 RAs are CNS penetrant; whether GLP-1 RAs reproducibly engage neural targets hypothesized to subserve dimensions of psychopathology (e.g., general cognitive functions) remains incompletely characterized.

Food intake serves to maintain energy homeostasis; however, overeating can result in obesity, which is associated with serious health complications. In this review, we explore the intricate relationship between overeating, obesity, and the underlying neurobiological mechanisms. We review the homeostatic and hedonic feeding systems, highlighting the role of the hypothalamus and reward systems in controlling food intake and energy balance. Dysregulation in both these systems leads to overeating, as seen in genetic syndromes and environmental models affecting appetite regulation when consuming highly palatable food. The concept of "food addiction" is examined, drawing parallels to drug addiction. We discuss the cellular substrate for addiction-related behavior and current pharmacological obesity treatments-in particular, GLP-1 receptor agonists-showcasing synaptic plasticity in the context of overeating and palatable food exposure. A comprehensive model integrating insights from addiction research is proposed to guide effective interventions for maladaptive feeding behaviors. Ultimately, unraveling the neurobiological basis of overeating holds promise for addressing the pressing public health issue of obesity.

The central nervous system (CNS) senses and integrates blood glucose status, regulating its levels through communication with peripheral organs. Since traditional wisdom holds that the hypothalamus primarily controls glucose homeostasis, the brainstem, although less studied, has been emerging as a key player in blood glucose metabolism. Although the brainstem is reciprocally wired with the hypothalamus, their interactions are crucial for glucose control. Here, we focus on classic discoveries and recent advancements of hypothalamic and brainstem nodes that regulate glucose homeostasis. Based on the current progress and development for central regulation of blood sugar, we propose that the circuitry and cellular mechanisms for how hypothalamus and brainstem coordinate in blood sugar regulation are crucial; hence, a deeper understanding of both nuclei could shed light on a future cure for diabetes.

Neurodegenerative diseases (NDDs) represent a heterogeneous group of disorders characterized by progressive neuronal loss, which results in significant deficits in memory, cognition, motor skills, and sensory functions. As the prevalence of NDDs rises, there is an urgent unmet need for effective therapies. Current drug development approaches primarily target single pathological features of the disease, which could explain the limited efficacy observed in late-stage clinical trials. Originally developed for the treatment of obesity and diabetes, incretin-based therapies, particularly long-acting GLP-1 receptor (GLP-1R) agonists and GLP-1R-gastric inhibitory polypeptide receptor (GIPR) dual agonists, are emerging as promising treatments for NDDs. Despite limited conclusive preclinical evidence, their pleiotropic ability to reduce neuroinflammation, enhance neuronal energy metabolism and promote synaptic plasticity positions them as potential disease-modifying NDD interventions. In anticipation of results from larger clinical trials, continued advances in next-generation incretin mimetics offer the potential for improved brain access and enhanced neuroprotection, paving the way for incretin-based therapies as a future cornerstone in the management of NDDs.

Hedonic eating is defined as food consumption driven by palatability without physiological need. However, neural control of palatable food intake is poorly understood. We discovered that hedonic eating is controlled by a neural pathway from the peri-locus ceruleus to the ventral tegmental area (VTA). Using photometry-calibrated optogenetics, we found that VTA dopamine (VTADA) neurons encode palatability to bidirectionally regulate hedonic food consumption. VTADA neuron responsiveness was suppressed during food consumption by semaglutide, a glucagon-like peptide receptor 1 (GLP-1R) agonist used as an antiobesity drug. Mice recovered palatable food appetite and VTADA neuron activity during repeated semaglutide treatment, which was reversed by consumption-triggered VTADA neuron inhibition. Thus, hedonic food intake activates VTADA neurons, which sustain further consumption, a mechanism that opposes appetite reduction by semaglutide.

We recently reported that a chimeric peptide (GEP44) targeting the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2- receptors decreased body weight (BW), energy intake, and core temperature in diet-induced obese (DIO) male and female mice. In the current study, we tested the hypothesis that the strong reduction in body weight in response to GEP44 is partially related to the stimulation of energy expenditure (EE). To test this, rats were maintained on a high fat diet (HFD) for at least 4 months to elicit DIO prior to undergoing a sequential 2-day vehicle period, 2-day GEP44 (50 nmol/kg) period, and a minimum 2-day washout period, and detailed measures of energy homeostasis. GEP44 (50 nmol/kg) reduced EE (indirect calorimetry), respiratory exchange ratio (RER), core temperature, activity, energy intake, and BW in male and female rats. As in our previous study in mice, GEP44 reduced BW in male and female HFD-fed rats by 3.8 ± 0.2% and 2.3 ± 0.4%, respectively. These effects appear to be mediated by increased lipid oxidation and reductions in energy intake as GEP44 reduced RER and cumulative energy intake in male and female HFD-fed rats. The strong reduction in body weight in response to GEP44 is related to a robust reduction in energy intake, but not to the stimulation of EE. The paradoxical finding that GEP44 reduced EE might be secondary to a reduction in diet-induced thermogenesis or might indicate an important mechanism to limit the overall efficacy of GEP44 to prevent further weight loss.

Evidence from previous research demonstrates a relationship between diabetes mellitus (DM) and Parkinson's disease (PD). T2DM is associated with chronic glucose dysregulation, as an etiological factor. It inhibits neuronal function through disrupted insulin signaling and oxidative stress, which ultimately lead to the loss of dopaminergic neurons in the substantia nigra (SN). Interactions between T2DM and PD were analyzed by gene expression, coexpression, and gene set enrichment via NCBI and STRING databases following pathways like KEGG and Reactome. The study identified nine key gene interactions through published literature on different databases and search engines that are involved in the progression of these chronic diseases. Furthermore, some genetic and nongenetic risk factors, gene mutations and environmental factors, are also involved in the progression of T2DM and PD. This review highlights the limitations of currently available drug treatments for these diseases and examines modern therapeutic approaches to address neurodegenerative and metabolic abnormalities. We critically assess the current experimental methodologies aimed at unraveling the pathophysiological mechanisms linking PD and T2DM while addressing the key challenges impeding a comprehensive understanding of the concurrent emergence of these debilitating age-related conditions.

Glucose-dependent insulinotropic polypeptide (GIP) is one of two incretin hormones playing key roles in the control of food intake, nutrient assimilation, insulin secretion and whole-body metabolism. Recent pharmacological advances and clinical trials show that unimolecular co-agonists that target the receptors for the incretins - GIP and glucagon-like peptide 1 (GLP-1) - offer more effective treatment strategies for obesity and type 2 diabetes mellitus (T2D) compared with GLP-1 receptor (GLP1R) agonists alone, suggesting previously underappreciated roles of GIP in regulating food intake and body weight. The mechanisms by which GIP regulates energy balance remain controversial as both agonism and antagonism of the GIP receptor (GIPR) produce weight loss and improve metabolic outcomes in preclinical models. Recent studies have shown that GIPR signalling in the central nervous system (CNS), especially in regions of the brain that regulate energy balance, is essential for its action on appetite regulation. This finding has sparked interest in understanding the mechanisms by which GIP engages brain circuits to reduce food intake and body weight. In this review, we present key knowledge around the actions of GIP on food intake regulation and the potential mechanisms by which GIPR and GIPR/GLP1R agonists may regulate energy balance.

Barriers of the central nervous system (CNS), such as the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), regulate the two-way exchange of material between the blood and CNS. These barriers pose a considerable challenge for efficacious delivery of intravenously administered therapies into the CNS, motivating exploration of their function and ways to modulate their properties. While the BBB and BCSFB can become dysfunctional in patients with chronic CNS diseases, few studies have focused on strategies for targeting these interfaces. Here, we showed that an intravenously administered albumin-binding lipid-siRNA conjugate was delivered to and silences genes within brain endothelial cells and choroid plexus epithelial cells, which comprise the BBB and BCSFB, respectively. A single intravenous dose of lipid-siRNA conjugate was delivered to ~100% of brain endothelial cells and major choroid plexus cell types, without any substantial delivery into brain parenchymal tissue. Sustained gene silencing was achieved in both brain endothelial cells (over two weeks) and bulk choroid plexus tissues (up to one month). Moreover, single cell RNA sequencing demonstrated gene knockdown in capillaries, venous endothelial cells, and choroid plexus epithelial cells without silencing genes in parenchymal cell populations. Collectively, this work establishes an effective nonviral framework to mediate gene inhibition in the brain barriers.

Tau hyper-phosphorylation has been recognized as an essential contributor to neurodegeneration in Alzheimer's disease (AD) and related tauopathies. In the last decade, tau hyper-phosphorylation has gained considerable concern in AD therapeutic development. Tauopathies are manifested with a broad spectrum of symptoms, from dementia to cognitive decline and motor impairments. Tau undergoes conformational changes and abnormal phosphorylation that mediate its detaching from microtubules, forming neurofibrillary tangles (NFTs). In the current study, a widely used P301S transgenic mice model of tauopathy was employed to evaluate the possible neuroprotective effects of semaglutide as an autophagy regulator through modifications of the brain renin-angiotensin system (RAS). Mice were divided into two groups according to their genotypes (wild type (Wt) and P301S), which were further subdivided to receive either vehicle (saline) or semaglutide (25 nmol/kg, i. p.), once every 2 days for 28 days. Current data suggest that semaglutide ameliorated the hyperactive pattern and alleviated the cognitive decline of P301S mice. It also hastened the autophagic flux through augmenting angiotensin-converting enzyme 2/sirtuin 1/forkhead box protein O1 signaling. Semaglutide also hindered the expression of phosphorylated adenosine monophosphate-activated protein kinase and phosphorylated glycogen synthase kinase-3 beta at serine 9, reducing the propagation of neuroinflammatory cytokines and oxidative reactions. Finally, semaglutide protected against hippocampal degeneration and reduced the immunoreactivity for total tau and ionized calcium-binding adapter molecule. Semaglutide showed promising neuroprotective implications in alleviating tauopathy-related AD's molecular and behavioral deficits through controlling autophagy and brain RAS.

Over the last 30 years, our understanding of the causes of obesity has been transformed, and new, highly effective medicines for reducing weight have been developed. This remarkable progress marks an end and a beginning. By establishing that obesity is a biologic disorder amenable to scientific inquiry and rational drug development, simplistic notions about its causes and treatment should be laid to rest. The future holds the promise that additional therapeutic approaches for inducing or maintaining weight loss will be developed, and that these treatments will be tailored to different subgroups to potentially address the pathogenic mechanisms.

Obesity is a chronic condition demanding effective treatment strategies, among which pharmacotherapy plays a critical role. As glucagon-like peptide-1 (GLP-1) agonist approved by the Food and Drug Administration (FDA) for long-term weight management in adults with obesity, liraglutide and semaglutide have great weight loss effect through reducing food intake and delaying gastric emptying. The emergence of unimolecular polypharmacology, which utilizes single molecules to simultaneously target multiple receptors or pathways, marked a revolutionary improvement in GLP-1-based obesity pharmacotherapy. The dual agonist tirzepatide activates both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors and has shown enhanced potency for weight loss compared to conventional GLP-1 mono agonist. Furthermore, emerging data suggests that unimolecular GLP-1/glucagon (GCG) dual agonist, as well as GLP-1/GIP/GCG triple agonist, may offer superior weight loss efficacy over GLP-1 agonist. This review summarizes the comprehensive mechanisms underlying the pronounced advantages of GLP-1/GIP dual agonist, GLP-1/GCG dual agonist and GLP-1/GIP/GCG triple agonist over GLP-1 mono agonist in weight reduction in obese adults without type 2 diabetes. A deeper understanding of these unimolecular multitargeting GLP-1-based agonists will provide insights for their clinical application and guide the development of new drugs for obesity treatment.

Obesity and its related complications are growing in prevalence worldwide, with increasing impact to individuals and healthcare systems alike. Currently, the leading treatment approaches for effective and sustained weight loss are bariatric surgery and gut peptide therapeutics. At a high level, both treatment strategies work by hijacking gut-brain axis signaling to reduce food intake. However, we predict that each modality has distinct neuronal mechanisms that are responsible for their success and complications. This review compares the neurobiology of feeding behavior between these two weight loss strategies via a discussion of both clinical and pre-clinical data. The most compelling evidence points to signaling within the hindbrain, hypothalamus, and reward circuits contributing to weight loss. Considerations for treatment, including differing complications between the two treatment approaches, will also be discussed. Based on the data, we pose the hypothesis that these two interventions are acting via distinct mechanisms to induce weight loss. Both interventions have variable degrees of weight loss across the patient population, thus, understanding these distinct mechanisms could help drive individualized medicine to optimize weight loss. This article is part of the Special Issue on "Food intake and feeding states".

Glucagon-like peptide-1 (GLP-1) analogs are approved for the treatment of obesity in adults and adolescents. Reports have emerged that the weight loss effect of these medications may be related to changes in food preferences and ingestive behaviors following the treatment. Understanding the mechanisms which impact ingestive behavior could expand opportunities to develop more refined and personalized treatment options for obesity.

Recent studies investigating the relationship between GLP-1 analogs and ingestive behaviors were retrieved from PubMed using the search terms: "obesity," "food preference," "taste," "ingestive behavior," "weight loss medication," "anti-obesity medication," "GLP-1 analog," "tirzepatide," "liraglutide," "semaglutide." Measurement tools were studied to compare variables used to assess food intake behavior. The main outcomes from each study were analyzed to evaluate the current standing and future directions of appetitive, ingestive, and consummatory behaviors and their association with GLP-1 analogs.

Thus far, studies have primarily explored the weight loss phase and report decreased short-term appetite and food intake upon treatment. However, research during the weight maintenance phase and objective measurements of food intake are notably sparse. Additionally, verbal reports have been primarily used to examine food intake, which can be susceptible to subjectivity.

Elucidating the relationship between GLP-1 analogs and ingestive behavior could reveal additional parameters which contribute to their anti-obesity effects. To better understand these mechanisms, it is imperative to consider objective measurements of food intake in future studies. Several measurement tools have been adapted to measure variables of food behavior in humans, and each must be carefully considered with their strengths and limitations to develop optimal investigations.

The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions1. However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies2,3. Here we combine single-nucleus sequencing of 433,369 human hypothalamic cells with spatial transcriptomics, generating a comprehensive spatio-cellular transcriptional map of the hypothalamus, the 'HYPOMAP'. Although conservation of neuronal cell types between humans and mice, as based on transcriptomic identity, is generally high, there are notable exceptions. Specifically, there are significant disparities in the identity of pro-opiomelanocortin neurons and in the expression levels of G-protein-coupled receptors between the two species that carry direct implications for currently approved obesity treatments. Out of the 452 hypothalamic cell types, we find that 291 neuronal clusters are significantly enriched for expression of body mass index (BMI) genome-wide association study genes. This enrichment is driven by 426 'effector' genes. Rare deleterious variants in six of these (MC4R, PCSK1, POMC, CALCR, BSN and CORO1A) associate with BMI at population level, and CORO1A has not been linked previously to BMI. Thus, HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context and serves as an important resource to identify new druggable targets for treating a wide range of conditions, including reproductive, circadian and metabolic disorders.

Weight regain and insufficient weight loss are essential problems after metabolic bariatric surgery (MBS) in people living with obesity. Changes in the level of glucagon-like peptide-1 (GLP-1) secreted from the gut after bariatric surgery are one of the underlying mechanisms for successful initial weight loss. Studies and meta-analyses have revealed that postprandial GLP-1 levels increase after the Roux-en-Y gastric bypass and sleeve gastrectomy, but fasting GLP-1 levels do not increase significantly. Some observational studies have shown the relationship between higher postprandial GLP-1 levels and successful weight loss after bariatric surgery. There is growing evidence that GLP-1-receptor agonist (GLP-1-RA) use in patients who regained weight after bariatric surgery has resulted in significant weight loss. In this review, we aimed to summarize the changes in endogenous GLP-1 levels and their association with weight loss after MBS, describe the effects of GLP-1-RA use on weight loss after MBS, and emphasize metabolic adaptations in light of the recent literature. We hypothesized that maintaining higher basal-bolus GLP-1-RA levels may be a promising treatment choice in people with obesity who failed to lose weight after bariatric surgery.

Postmenopausal osteoporosis is a common chronic medical illness resulting from an imbalance between bone resorption and bone formation along with microarchitecture degeneration attributed to estrogen deficiency and often accompanied by other medical conditions such as weight gain, depression, and insomnia. Semaglutide (SEM) is a recently introduced GLP-1 receptor agonist (GLP-1RA) for the treatment of obesity and type 2 diabetes mellitus by mitigating insulin resistance. It has been discovered that the beneficial effects of GLP-1 are associated with alterations in lipolysis, adipogenesis, and anti-inflammatory processes. GLP-1 analogs transmit signals directly to adipose tissue. Mesenchymal stem cells (MSCs) are multidisciplinary cells that originate from bone marrow, migrate to injury sites, and promote bone regeneration. MSCs can differentiate into osteoblasts, adipose cells, and cartilage cells. Our aim is to investigate the role of semaglutide on bone formation and the Wnt signaling pathway. Osteoporosis was induced in female rats by ovariectomy, and the ovariectomized rats were treated with alendronate as standard treatment with a dose of 3 mg/kg orally and semaglutide with two doses (150 mcg/kg and 300 mcg/kg) S.C. for 10 successive weeks. Semaglutide ameliorates bone detrimental changes induced by ovariectomy. It improves bone microarchitecture and preserves bone mineral content. Semaglutide ameliorates ovariectomy-induced osteoporosis and increases the expression of β-catenin, leading to increased bone formation and halted receptor activator of nuclear factor kappa-Β ligand (RANKL's) activation. Semaglutide can be used as a potential prophylactic and therapeutic drug against osteoporosis, possibly by activating Wnt signaling and decreasing bone resorption.