Inverse Association Between Hypothalamic N-Acetyl Aspartate/Creatine Ratio and Indices of Body Mass in Adolescents with Obesity.

BACKGROUND: Approximately 10% of adolescents worldwide are overweight or obese, hence the urgent and universal need to elucidate possible mechanisms that lead to obesity in the adolescent population. OBJECTIVES: We examined the hypothalamic metabolism and its relationship with physical development in obese and eutrophic adolescents. METHODS: We performed a case-control study with 115 adolescents between 11 and 18 years of age, to compare obese (BMI z-score ≥ 2) and nonobese individuals (eutrophic controls; BMI z-score ≤ 1). The following hypothalamic metabolite ratios were examined as primary outcomes: glutamate/creatine (Cr), the sum of glutamate and glutamine/Cr, N-acetylaspartate (NAA)/Cr, myoinositol/Cr, and total choline/Cr (glycerophosphocholine +  phosphocholine/Cr), quantified by magnetic resonance spectroscopy. BMI z-scores, pubertal status, and scores on the Yale Food Addiction Scale, the Binge Eating Scale, and the Child Depression Inventory were assessed as secondary outcomes. Pearson coefficients (r) or nonparametric Spearman correlation (rho) analyses were performed between hypothalamic metabolite ratios and other parameters, such as BMI z-scores, physical development, food habits, depression symptoms, and serum protein concentrations (cytokines, hormones, and neuropeptides). RESULTS: Adolescents with obesity showed a lower hypothalamic NAA/Cr ratio (0.70 ± 0.19) compared to their eutrophic counterparts (0.84 ± 0.20; P = 0.004). The NAA/Cr ratio was negatively correlated with BMI z-scores (r = -0.25; P = 0.03) and serum insulin (rho = -0.27; P = 0.04), C-peptide (rho = -0.26; P = 0.04), amylin (r = -0.27; P = 0.04), ghrelin (rho = -0.30; P = 0.02), and neuropeptide Y (r = -0.27; P = 0.04). Also, the NAA/Cr ratio was positively correlated with circulating IL-8 levels (rho = 0.26; P = 0.04). CONCLUSIONS: High BMI z-scores are associated with lower hypothalamic NAA/Cr ratios. The negative correlations found between the NAA/Cr ratio and serum cytokines, hormones, and neuropeptides suggest a broad cross-talk linking hormonal imbalances, neurohumoral alterations, and hypothalamic functions in adolescents with obesity.

Sex dimorphism in inflammatory response to obesity in childhood.

BACKGROUND: Childhood overweight and obesity are a global concern, with prevalence rising dramatically over the last decades. The condition is caused by an increase in energy intake and reduction of physical activity, leading to excessive fat accumulation, followed by systemic chronic inflammation and altered function of immune cell responses. This study aimed at providing new insights regarding sex-specificity on the inflammatory response to obesity in the young patient. DESIGN: Forty-three Brazilian obese adolescents (Female = 22 and Male=21, BMI (body mass index) Z-score average = 2.78 ± 0.51) and forty-nine eutrophic adolescents (Female = 24 and Male = 25, BMI Z-score average = -0.35 ± 0.88) were enrolled in the study. Anthropometrical analyses and blood cell counts were carried out. Using Luminex®xMAP™ technology, circulating serum cytokines, chemokines, and inflammatory biomarkers were analyzed. Two-way ANOVA test, Tukey's test, and Spearman's correlation coefficient were employed, with a significance threshold set at p < 0.05. RESULTS: We identified increased levels of serum amyloid A (SAA), platelets, and leukocytes solely in male obese patients. We found a noteworthy sex-dependent pattern in regard to inflammatory response: obese boys showed higher TNFß, IL15, and IL2 and lower IL10 and IL13, while obese girls showed increased TNFα, CCL3, CCL4, and IP10 content in the circulation. BMI Z-score was significantly linearly correlated with neutrophils, leukocytes, platelets, SAA, TNFα, CCL3, CCL4, IP10, and IL13 levels within the entire cohort (non-sex-dependent). CONCLUSIONS: Our data support a complex relationship between adiposity, blood cell count, and circulating inflammatory cytokine content. High SAA levels suggest that this factor may play a critical role in local and systemic inflammation. In the eutrophic group, females presented a lower status of inflammation, as compared to males. Both obese boys and girls showed an increased inflammatory response in relation to eutrophic counterparts. Taken together, results point out to clear sex dimorphism in the inflammatory profile of obese adolescents.

Myokines in treatment-naïve patients with cancer-associated cachexia.

Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways.

Immediate effects of a real moderate interval-running training session on inflammatory profile.

The study investigated the immediate effect of a moderate interval-running training session on circulating inflammatory cytokines concentration at real conditions of training. Nine recreational runners (5 women and 4 men; 68,33 ± 10,20 kg; 1,65 ± 0,07 m; 28,67 ± 4,24 years) had blood samples collected from antecubital vein before and immediately after a moderate interval-running training session without fasting. Cytokine levels were obtained from blood samples through Multiplex Analysis of Sample Protein Content, performed by Magpix® instrument. The assay detected the cytokines and calculated the plasma cytokine concentrations. Reduced concentration was observed after training session for all cytokines (p < 0.05), except for IP-10. Moderate effect sizes were identified in IL-6, IL-8, TNF-α, IP-10, MCP1 and GM-CSF. In summary, a single moderate interval-running training session at real conditions of training seems not to be stressing enough to increase cytokine levels as a response to the exercise. Results reinforce that immediate biochemical response and inflammatory modulation related to exercise is dose-dependent and may be influenced by other variables.

Sex-Dependent Dyslipidemia and Neuro-Humoral Alterations Leading to Further Cardiovascular Risk in Juvenile Obesity.

Objective: Childhood obesity is a growing concern as the World Health Organization (WHO) states that ~10% of adolescents worldwide are overweight or obese. This condition is the reflex of energy imbalance between the calories consumed and those expended. Sex-related responses associated with dyslipidemia, hormonal alterations, and neuro-humoral disruptions in childhood obesity are the focus of the present investigation. Methods: Ninety-two Brazilian adolescents were enrolled and divided between obese and eutrophic groups. Obesity was assessed using body mass index Z-score according to age and weight. Anthropometrical analyses, blood pressure, blood lipids, metabolism-regulating hormones, and neuropeptides were carried out. Results: Systolic blood pressure was higher in female and male patients with obesity. Obese females presented alterations in lipid profile and an augment of cardiovascular disease prediction ratios TC/HDL, TG/HDL, LDL/HDL, and VLDL/HDL. The levels of leptin, GIP, and neuropeptide showed sex-dimorphism in obesity. The obese adolescents presented increased levels of circulating insulin, c-peptide, amylin, glucagon, and GLP-1. Correlation analysis showed significant linearity between body mass index, blood pressure, lipids, lipoproteins, hormones, and neuropeptides content. Conclusions: Our data support an existing link associating hypertension, dyslipidemia, and neuro-hormonal imbalance in childhood obesity. We also described a sex-dependent pattern in childhood obesity-associated dyslipidemia and blood pressure in female patients with obesity solely.

Dectin-1 Activation Exacerbates Obesity and Insulin Resistance in the Absence of MyD88.

The underlying mechanism by which MyD88 regulates the development of obesity, metainflammation, and insulin resistance (IR) remains unknown. Global deletion of MyD88 in high-fat diet (HFD)-fed mice resulted in increased weight gain, impaired glucose homeostasis, elevated Dectin-1 expression in adipose tissue (AT), and proinflammatory CD11c+ AT macrophages (ATMs). Dectin-1 KO mice were protected from diet-induced obesity (DIO) and IR and had reduced CD11c+ AT macrophages. Dectin-1 antagonist improved glucose homeostasis and decreased CD11c+ AT macrophages in chow- and HFD-fed MyD88 KO mice. Dectin-1 agonist worsened glucose homeostasis in MyD88 KO mice. Dectin-1 expression is increased in AT from obese individuals. Together, our data indicate that Dectin-1 regulates AT inflammation by promoting CD11c+ AT macrophages in the absence of MyD88 and identify a role for Dectin-1 in chronic inflammatory states, such as obesity. This suggests that Dectin-1 may have therapeutic implications as a biomarker for metabolic dysregulation in humans.

Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ.

BACKGROUND: CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. OBJECTIVES: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. METHODS: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. RESULTS: Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients. CONCLUSION: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.