Liver function parameters, cholesterol, and phospholipid α-linoleic acid are associated with adipokine levels in overweight and obese adults

Dysregulation of adipose hormones in obesity has been associated with the hastened development of metabolic syndrome and associated chronic disease sequalae including cardiovascular disease and type 2 diabetes mellitus. This study aims to identify common biochemical and anthropometric markers that impact adipose hormones, including adiponectin and leptin. Based on previous literature, it was hypothesized that these would be adversely impacted by liver function parameters, and adiponectin levels would be positively correlated with phospholipid Ω-3 fatty acids. Forty nondiabetic adult subjects (body mass index, ≥25.0 kg/m2) were recruited. Fasting plasma samples were taken to assess adipokine levels, glucose metabolism, electrolytes, liver enzymes, and blood lipids. Basic anthropometric measurements were also recorded. Adiponectin levels were positively correlated with high-density lipoprotein cholesterol and negatively correlated with anthropometric measures, insulin, liver enzymes, triglycerides, and very low-density lipoprotein cholesterol but not body mass index. Conversely, plasma leptin levels were positively correlated with anthropometric measures, C-reactive protein, high-density lipoprotein cholesterol, and plasma phospholipid proportions of Ω-3 α linoleic acid but inversely correlated with creatinine levels. These results support other data regarding correlations between adiponectin and relative adipose distribution. Correlations with specific liver enzymes may indicate that adiponectin levels are tied to fatty acid deposition in the liver; however, liver/kidney damage though further mechanistic clarification is required. Leptin levels were associated with measures of adiposity but not liver enzymes. Each of these variables, along with blood lipids, may serve as potential future therapeutic targets for the prevention and management of obesity and related comorbidities

Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterioration of motor neurons. However, this complex disease extends beyond the boundaries of the central nervous system, with metabolic alterations being observed at the systemic and cellular level. While the number of studies that assess the role and impact of metabolic perturbations in ALS is rapidly increasing, the use of metabolism biomarkers in ALS remains largely underinvestigated. In this review, we discuss current and potential metabolism biomarkers in the context of ALS. Of those for which data does exist, there is limited insight provided by individual markers, with specificity for disease, and lack of reproducibility and efficacy in informing prognosis being the largest drawbacks. However, given the array of metabolic markers available, the potential exists for a panel of metabolism biomarkers, which may complement other current biomarkers (including neurophysiology, imaging, as well as CSF, blood and urine markers) to overturn these limitations and give rise to new diagnostic and prognostic indicators

In vivo pharmacological evaluation of a lactose-conjugated luteinizing hormone releasing hormone analogue

In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q][w]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (C = 0.11 μg/ml) was reached at 2 h (T) following oral administration of the compound at 10 mg/kg. The half-life was determined to be 2.6 h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-to-low oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20 mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 μg/ml and a correlation coefficient of r ≥ 0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases

Actions of NPY, and its Y1 and Y2 receptors on pulsatile growth hormone secretion during the fed and fasted state

The hypothalamic NPY system plays an important role in regulating food intake and energy expenditure. Different biological actions of NPY are assigned to NPY receptor subtypes. Recent studies demonstrated a close relationship between food intake and growth hormone (GH) secretion; however, the mechanism through which endogenous NPY modulates GH release remains unknown. Moreover, conclusive evidence demonstrating a role for NPY and Y-receptors in regulating the endogenous pulsatile release of GH does not exist. We used genetically modified mice (germline Npy, Y1, and Y2 receptor knock-out mice) to assess pulsatile GH secretion under both fed and fasting conditions. Deletion of NPY did not impact fed GH release; however, it reversed the fasting-induced suppression of pulsatile GH secretion. The recovery of GH secretion was associated with a reduction in hypothalamic somatotropin release inhibiting factor (Srif; somatostatin) mRNA expression. Moreover, observations revealed a differential role for Y1 and Y2 receptors, wherein the postsynaptic Y1 receptor suppresses GH secretion in fasting. In contrast, the presynaptic Y2 receptor maintains normal GH output under long-term ad libitum-fed conditions. These data demonstrate an integrated neural circuit that modulates GH release relative to food intake, and provide essential information to address the differential roles of Y1 and Y2 receptors in regulating the release of GH under fed and fasting states

Transgenic Adipose-specific Expression of the Nuclear Receptor RORα Drives a Striking Shift in Fat Distribution and Impairs Glycemic Control.

RORα is a member of the nuclear receptor (NR) superfamily and analysis of the (global) RORα-deficient mouse model revealed this NR has a role in glycemic control and fat deposition. Therefore, we generated an adipose-specific RORα 'gain of function' mouse model under the control of the fatty acid binding protein 4 (FABP4) promoter to elucidate the function of RORα in adipose tissue. The Tg-FABP4-RORα4 mice demonstrated a shift in fat distribution to non-adipose tissues when challenged with a high fat diet (HFD). Specifically, we observed a subcutaneous lipodystrophy, accompanied by hepatomegaly (fatty liver/mild portal fibrosis) and splenomegaly; in a background of decreased weight gain and total body fat after HFD. Moreover, we observed significantly higher fasting blood glucose and impaired clearance of glucose in Tg-FABP4-RORα4 mice. Genome wide expression and qPCR profiling analysis identified: (i) subcutaneous adipose specific decreases in the expression of genes involved in fatty acid biosynthesis, lipid droplet expansion and glycemic control, and (ii) the fibrosis pathway as the most significant pathway [including dysregulation of the collagen/extracellular matrix (ECM) pathways] in subcutaneous adipose and liver. The pathology presented in the Tg-FABP4-RORα4 mice is reminiscent of human metabolic disease (associated with aberrant ECM expression) highlighting the therapeutic potential of this NR

Thyroid-stimulating hormone pulses finely tune thyroid hormone release and TSH receptor transduction

Detection of circulating thyroid-stimulating hormone (TSH) is a first-line test of thyroid dysfunction, a major health problem (affecting about 5% of the population) that, if untreated, can lead to a significant deterioration of quality of life and adverse effects on multiple organ systems. Human TSH levels display both pulsatile and (non-pulsatile) basal TSH secretion patterns; however, the importance of these in regulating thyroid function and their decoding by the thyroid is unknown. Here, we developed a novel ultra-sensitive ELISA that allows precise detection of TSH secretion patterns with minute resolution in mouse models of health and disease. We characterised the patterns of ultradian TSH pulses in healthy, freely-behaving mice over the day-night cycle. Challenge of the thyroid axis with primary hypothyroidism due to iodine deficiency, a major cause of thyroid dysfunction worldwide, results in alterations of TSH pulsatility. Induction in mouse models of sequential TSH pulses that mimic ultradian TSH profiles in periods of minutes were more efficient than sustained rises in basal TSH levels at increasing both thyroid follicle cAMP levels, as monitored with a genetically-encoded cAMP sensor, and circulating thyroid hormone (TH). Hence this mouse TSH assay provides a powerful tool to decipher how ultradian TSH pulses encode thyroid outcomes, and to uncover hidden parameters in the TSH-TH set-point in health and disease.</p

Non-invasive assessment of altered activity following restraint in mice using an automated physiological monitoring system

In the laboratory setting, typical endocrine and targeted behavioral tests are limited in their ability to provide a direct assessment of stress in animals housed in undisturbed conditions. We hypothesized that an automated phenotyping system would allow the detection of subtle stress-related behavioral changes well beyond the time-frames examined using conventional methods. In the present study, we have utilized the TSE PhenoMaster system to continuously record basal behaviors and physiological parameters including activity, body weight, food intake, and oxygen consumption in undisturbed and stressed C57Bl/6J male mice (n = 12/group), with a pharmacological intervention using the conventional anxiolytic, diazepam (5 mg kg−1 i.p.; n = 8/group). We observed significant 20-30% reductions in locomotor activity in the dark phase, with subtle reductions in light phase activity for up to 96 hours following a single 2 hour episode of restraint stress. A single administration of diazepam reduced plasma corticosterone concentrations by 30-35% during stress exposure when compared to mice treated with vehicle. This treatment did not result in significantly different locomotor activity compared to vehicle within the first 48 hours following restraint stress. However, diazepam treatment facilitated restoration of locomotor activity at 72 and 96 hours after restraint stress exposure in comparison to vehicle-treated mice. Hence, the use of an automated phenotyping system allows a real time assessment of basal behaviors and empirical metabolism following exposure to restraint stress and demonstrates major and subtle changes in activity persist for several days after stress exposure

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology