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The obesity pandemic continues to increase in prevalence in children and adolescents, with its increase outpacing the rate of adult obesity; the human developmental index, body mass index, and family income all display associations to childhood obesity. There are numerous adverse complications of childhood obesity, including cardiovascular, endocrine, and gastrointestinal manifestations. Obesity is thought to be an interaction of several different factors, such as leptin, proopiomelanocortin, glucose uptake in adipocytes, melanocortin receptor 4, protein convertase 1/3, brain-derived neurotrophic factor, fat-mass and obesity-associated gene, melanocortin receptor 4, tumor necrosis factor, interleukin-6, and long noncoding RNA. Epigenetic regulation, the unique gut microbiome role in contributing to obesity, environmental factors, and the social context of a child can precipitation of childhood obesity. In this review, we hope to explore the different medications for obesity, orlistat, glucagon-like peptide-1 agonists, liraglutide, semaglutide, exenatide, setmelanotide, metreleptin, naltrexone, lorcaserin, phentermine, metformin, fluoxetine, lisdexamfetamine, and zonisamide, while also reviewing surgeries such as the Roux-en-Y gastric bypass, laparoscopic or vertical sleeve gastrectomy, and adjustable gastric banding. Show less

Obesity and excessive weight gain have emerged as significant global health concerns in recent years and are often comorbid with numerous contemporary diseases, including cardiovascular disorders, diabetes, and cognitive impairments. L-carnitine, a vital cofactor in mitochondrial energy metabolism, possesses potent antioxidant and anti-inflammatory properties that merit investigation for mitigating obesity-associated neuronal damage. Consequently, this study investigated the potential neuroprotective effects of L-carnitine on anxiety- and depression-like behaviors in adolescent rats subjected to neonatal monosodium glutamate (MSG) exposure, a model known to induce obesity and associated neurobehavioral alterations. Neonatal rats received MSG (4 g/kg, s.c.) on alternate postnatal days (PND) 2-10. Subsequently, L-carnitine (200 mg/kg) was administered via oral gavage daily from PND 60 to 81 (subchronic treatment). Anxiety- and depression-like behaviors were assessed using the Forced Swim Test (FST), Elevated Plus Maze (EPM), and Open Field Test (OFT). All molecular and histological analyses were conducted in the prefrontal cortex (PFC), a region selected for its susceptibility to excitotoxicity and critical role in emotional regulation. Oxidative stress was evaluated through measurements of total oxidant and antioxidant levels. To elucidate the underlying molecular mechanisms, gene expression analyses focused on neuronal survival and apoptosis (BDNF, Bax, Bcl-2), while immunohistochemical evaluations targeted neuroinflammation and cell death pathways (TNF-α, Caspase-3, IL-1β, and Bcl-2). The findings reveal that neonatal MSG exposure leads to pronounced anxiety- and depression-like behaviors, accompanied by metabolic dysregulation, oxidative stress, neuroinflammation, and apoptosis. Although L-carnitine treatment did not reverse obesity-related metabolic alterations, it exhibited notable sustained anxiolytic effects. The neuroprotective potential of L-carnitine was further supported by its ability to reduce cortical neuroinflammation and neurodegerenative damage through suppression of proinflammatory cytokines and restoration of antioxidant balance. Overall, this study offers valuable insights into the cognitive, genetic, and histological outcomes associated with obesity-related mood disturbances and contributes to understanding the complex biological mechanisms underlying these conditions. Show less

A single nucleotide polymorphism in the brain derived neurotrophic factor (BDNF)-encoding gene leads to diminished BDNF signaling resulting from Val66Met and has been linked to obesity. Previous imaging studies regarding the impact of BDNF Val66Met on the central serotonin system, which is involved in behavior, cognition and control of satiety, have not focused on body weight or food-intake related behavior. We revisited a cohort of thirty non-depressed individuals with obesity and 15 normal-weight controls. 29 obese and 13 controls underwent [ Show less

Brain-derived neurotrophic factor (BDNF) is a neurotrophin important for neuronal survival and synaptic plasticity that also plays a role in metabolic regulation (energy homeostasis and appetite control). Lower circulating BDNF levels have been associated with obesity, metabolic risk factors, and poorer cognitive and mental health outcomes, whereas higher levels are linked to more favorable profiles. In this study we sought to systematically evaluate the effects of dietary weight-loss interventions on circulating BDNF levels in adults with overweight or obesity. A comprehensive literature search of PubMed, Web of Science, Scopus, and Google Scholar was conducted from inception through April 2025 to identify clinical trials investigating dietary weight-loss or calorie-restriction interventions in adults with overweight or obesity that reported data regarding circulating BDNF outcomes. Eligible studies were clinical trials with interventions lasting ≥4 weeks to investigate circulating BDNF concentrations before and after dietary interventions that were conducted in adults (≥18 years old) with baseline overweight or obesity. This systematic review was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Risk of bias was assessed using the Cochrane risk-of-bias tool. Data on study design, participant characteristics, dietary interventions, and BDNF outcomes were extracted and synthesized qualitatively. A summary table of the included studies was generated. Fifteen clinical studies (n = 862 total participants) met inclusion criteria (11 randomized trials and 4 single-arm trials). Diet modalities included continuous calorie restriction (typically 20%-30% caloric deficit), intermittent fasting (eg, alternate-day fasting, time-restricted eating), ketogenic diets (KDs), Mediterranean-type diets, and other weight-loss diets. Duration of interventions ranged from 6 to 26 weeks. Responses to BDNF varied by intervention. In adults with overweight/obesity, weight-loss dietary interventions demonstrated heterogeneous effects on circulating BDNF. We categorized the included studies into 3 groups based on the effects of dietary weight loss on BDNF: increases, no significant change, or decreases. Approximately half of the studies showed no significant effect, while a few interventions showed a decrease. Intermittent fasting regimens and certain dietary patterns (eg, the Mediterranean-DASH [Dietary Approaches to Stop Hypertension] [MIND] diet, and the KD) tend to elevate BDNF levels, whereas continuous calorie restriction often shows no change, and very rapid weight loss may paradoxically reduce BDNF in some cases. These findings suggest that diet-induced weight loss can influence neurotrophic status, potentially modulating brain health. However, results are inconsistent across studies. Overall, interventions involving intermittent calorie restriction, MIND, and/or KD, more frequently reported BDNF increases, whereas continuous calorie restriction produced mixed results. Show less

Symptomatic neuromas result from disorganized nerve growth at the site of amputation, causing pain that affects recovery and quality of life. In patients with diabetes mellitus (DM), nerve regeneration is impaired, compounded by comorbidities such as obesity, hypertension, and hyperlipidemia. Surgical approaches including targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) have shown promise for managing symptomatic neuroma, but their effectiveness in diabetic patients is uncertain due to unique challenges in nerve regeneration. This narrative review explores the protective effects of DM on symptomatic neuroma formation and to evaluate the implications for surgical intervention. A systematic search of PubMed was conducted, and relevant studies discussing symptomatic neuroma formation in amputees were included. Symptomatic neuromas were reported in 9.5-50% of amputees involving 9.5% of upper extremity, and 3.8% of lower extremity amputees. Younger age and proximal amputations were identified as significant risk factors. While it is suggested that Interleukin (IL)-10 and brain-derived neurotropic factor (BDNF) levels are involved in protecting against symptomatic neuroma formation, IL-1β and IL-6 promote neuroma formation. Although evidence is mixed, some evidence suggests that DM and diabetic peripheral neuropathy decrease symptomatic neuroma formation by impairing axonal regeneration, altering the extracellular matrix and modulating inflammatory responses. Although surgical approaches such as TMR and RPNI have shown potential in reducing neuroma-related pain, further studies are needed to ensure that this benefit extends to diabetic patients whose disease puts them at increased risk of postoperative complications. Additional studies are required to confirm these findings and optimize surgical strategies for high-risk patient populations. Show less

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus (T2DM) and obesity, show promising potential as a novel treatment for depression, particularly in patients with comorbid metabolic disorders. This narrative review examines the bidirectional relationship between obesity and depression, driven by shared mechanisms such as chronic low-grade inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and impaired neuroplasticity. GLP-1 RAs, including liraglutide and exenatide, demonstrate neuroprotective effects by enhancing brain-derived neurotrophic factor expression and synaptic plasticity, alongside anti-inflammatory properties that reduce proinflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6). They also modulate serotonin turnover in mood-regulating brain regions, mirroring selective serotonin reuptake inhibitors. Preclinical studies in animal models reveal improved behavioral outcomes, while human observational studies and limited clinical trials, such as the LEAD-3 trial, report enhanced mood and quality of life in T2DM and obesity patients. However, challenges, including high treatment costs ($800-$1000/month), injectable administration, and needle-related anxiety, limit patient adherence, and clinical adoption. The lack of large-scale randomized controlled trials targeting depression as a primary outcome further hinders definitive conclusions. This review highlights GLP-1 RAs' potential to address both metabolic and depressive symptoms, offering a holistic approach to managing these interconnected conditions. Future research should focus on long-term efficacy, optimal dosing, and overcoming adherence barriers to establish GLP-1 RAs as a viable psychiatric treatment. Show less

The effects of different exercise intensities on cognitive outcomes and brain-derived neurotrophic factor (BDNF) concentrations in adolescents with overweight/obesity are not yet fully elucidated. This study aimed: (a) to compare the prevalence of responders to cognitive function and BDNF concentration in adolescents with overweight/obesity participating in a 12-week intervention with high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), and (b) to analyze whether cardiorespiratory fitness (CRF) can explain differences in inter-individual variability between responders and non-responders. Adolescents with overweight/obesity were assigned to HIIT (n = 15), MICT (n = 14), or CG (n = 24). Anthropometrics, body composition, CRF, basal BDNF, and cognitive performance (Trial Making Test (TMT) and Stroop Test (ST)) were evaluated pre- and post-intervention. Training was performed on stationary bikes (3×/week for 12 weeks). The prevalence of responders in ST and TMT was higher in the HIIT group than in CG (93-62%, p = 0.029; 67-33%, p = 0.043), with no differences in MICT. No group differences were found for BDNF responders (HIIT:73%-MICT:71%-CG:46%, p = 0.263). ST and TMT responders had greater CRF improvements than non-responders. HIIT elicited a higher prevalence of cognitive responders than CG. CRF improvements may partially explain individual variability in responsiveness to cognitive outcomes. This is the first study to examine and compare inter-individual variability in cognitive function and BDNF levels following MICT and HIIT interventions in adolescents with overweight/obesity; Exercise intensity and improvements in cardiorespiratory fitness are key factors for optimizing the cognitive effects of interventions in youth with overweight; Twelve weeks of supervised HIIT and MICT training led to increased rates of cognitive responders among adolescents with overweight/obesity. Show less

High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK-ERK-CREB-BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline. Show less

Obesity is closely associated with cognitive dysfunction, and markedly increases the risk of developing neurodegenerative diseases. Currently, obesity-related cognitive impairment lacks effective therapeutic interventions. Shenling Baizhu Powder (SLBZ) is a classical formula used to strengthen the spleen and promote the ascent of clear qi in traditional Chinese medicine (TCM). According to the TCM, this formula has great potential for the treatment of obesity-related cognitive impairment. However, research on SLBZ has focused primarily on its gastrointestinal effects, leaving its neurocognitive mechanisms largely unexplored. This study aimed to elucidate the therapeutic mechanisms of SLBZ in obesity-related cognitive impairment. Obese mice were obtained by subjecting male mice to a 16-week high-fat diet (HFD, 60 kcal % fat). During the final four weeks of the study, a SLBZ decoction (10 and 20 g/kg/day) was administered orally. The mice were then subjected to two behavioral tests and a glucose tolerance test. To evaluate the therapeutic effects of HFD on metabolic dysregulation, neuroinflammation, and intestinal barrier impairment, a range of analytical techniques, including biochemical analysis, immunofluorescence, RT-qPCR, and Western blotting, were used. Subsequently, 16S rRNA gene sequencing and metabolomic profiling were used to detect changes in the gut microbes and metabolite levels. Finally, fecal microbiota transplantation was performed to assess the functional link between SLBZ remodeling of the gut microbiota, metabolic alterations, and hippocampal cognitive function. Our study demonstrated that HFD-fed mice developed significant cognitive impairment, supporting the notion that obesity adversely affects cognitive function. In the Morris water maze and open-field tests, SLBZ administration effectively ameliorated HFD-induced cognitive dysfunction. This improvement was accompanied by the restoration of the hippocampal synaptic ultrastructure and the recovery of the key synaptic proteins BDNF and PSD95. In agreement with this, SLBZ suppressed microglial activation and associated neuroinflammatory responses in HFD-fed mice. In the colon, SLBZ administration markedly alleviated HFD-induced gut barrier impairment, as evidenced by increased colonic mucus thickness and elevated expression of tight junction proteins, ZO-1, Occludin, and Claudin-1. Furthermore, SLBZ reduced endotoxin translocation and downregulated the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. Notably, HFD-induced gut microbiota dysbiosis was remodeled by the SLBZ treatment, which was characterized by an increased capacity for microbial vitamin B6 synthesis. SLBZ increased the serum levels of vitamin B6 in HFD-fed mice. Intriguingly, fecal microbiota transplantation from SLBZ-treated HFD-fed mice facilitated the amelioration of cognitive deficits, including superior performance in behavioral tests and synaptic repair in the hippocampus compared to recipients of HFD-microbiota. Our findings highlight that SLBZ is a promising therapeutic agent mitigating obesity-related cognitive impairment via the "gut microbiota-vitamin B6-neuroprotection" axis. Show less