Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

GQ-11: A new PPAR agonist improves obesity-induced metabolic alterations in LDLr-/- mice.

BACKGROUND: Obesity and insulin resistance/diabetes are important risk factors for cardiovascular diseases and demand safe and efficacious therapeutics. OBJECTIVE: To assess the effects of a new thiazolidine compound-GQ-11-on obesity and insulin resistance induced by a diabetogenic diet in LDL receptor-deficient (LDLr-/-) mice. METHODS: Molecular docking simulations of GQ-11, PPARα and PPARγ structures were performed. Male C57BL/6J LDLr-/- mice fed a diabetogenic diet for 24 weeks were treated with vehicle, GQ-11 or pioglitazone or (20 mg/kg/day) for 28 days by oral gavage. Glucose tolerance test, insulin, HOMA-IR, adipokines (leptin, adiponectin) and the lipid profile were assessed after treatment. Adipose tissue was analysed by X-ray analysis and morphometry; gene and protein expression were evaluated by real-time PCR and western blot, respectively. RESULTS: GQ-11 showed partial agonism to PPARγ and PPARα. In vivo, treatment with GQ-11 ameliorated insulin sensitivity and did not modify subcutaneous adipose tissue and body weight gain. In addition, GQ-11 restored adipokine imbalance induced by a diabetogenic diet and enhanced Glut-4 expression in the adipose tissue. Improved insulin sensitivity was also associated with lower levels of MCP-1 and higher levels of IL-10. Furthermore, GQ-11 reduced triglycerides and VLDL cholesterol and increased HDL-cholesterol by upregulation of Apoa1 and Abca1 gene expression in the liver. CONCLUSION: GQ-11 is a partial/dual PPARα/γ agonist that demonstrates anti-diabetic effects. Additionally, it improves the lipid profile and ameliorates chronic inflammation associated with obesity in atherosclerosis-prone mice.

Serum Amyloid A Production Is Triggered by Sleep Deprivation in Mice and Humans: Is That the Link between Sleep Loss and Associated Comorbidities?

Serum amyloid A (SAA) was recently associated with metabolic endotoxemia, obesity and insulin resistance. Concurrently, insufficient sleep adversely affects metabolic health and is an independent predisposing factor for obesity and insulin resistance. In this study we investigated whether sleep loss modulates SAA production. The serum SAA concentration increased in C57BL/6 mice subjected to sleep restriction (SR) for 15 days or to paradoxical sleep deprivation (PSD) for 72 h. Sleep restriction also induced the upregulation of Saa1.1/Saa2.1 mRNA levels in the liver and Saa3 mRNA levels in adipose tissue. SAA levels returned to the basal range after 24 h in paradoxical sleep rebound (PSR). Metabolic endotoxemia was also a finding in SR. Increased plasma levels of SAA were also observed in healthy human volunteers subjected to two nights of total sleep deprivation (Total SD), returning to basal levels after one night of recovery. The observed increase in SAA levels may be part of the initial biochemical alterations caused by sleep deprivation, with potential to drive deleterious conditions such as metabolic endotoxemia and weight gain.

Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice.

AIMS/HYPOTHESIS: Pre-adipocytes and adipocytes are responsive to the acute phase protein serum amyloid A (SAA). The combined effects triggered by SAA encompass an increase in pre-adipocyte proliferation, an induction of TNF-α and IL-6 release and a decrease in glucose uptake in mature adipocytes, strongly supporting a role for SAA in obesity and related comorbidities. This study addressed whether SAA depletion modulates weight gain and insulin resistance induced by a high-fat diet (HFD). METHODS: Male Swiss Webster mice were fed an HFD for 10 weeks under an SAA-targeted antisense oligonucleotide (ASOSAA) treatment in order to evaluate the role of SAA in weight gain. RESULTS: With ASOSAA treatment, mice receiving an HFD did not differ in energy intake when compared with their controls, but were prevented from gaining weight and developing insulin resistance. The phenotype was characterised by a lack of adipose tissue expansion, with low accumulation of epididymal, retroperitoneal and subcutaneous fat content and decreased inflammatory markers, such as SAA3 and toll-like receptor (TLR)-4 expression, as well as macrophage infiltration into the adipose tissue. Furthermore, a metabolic status similar to chow-fed mice counterparts could be observed, with equivalent levels of leptin, adiponectin, IGF-I, SAA, fasting glucose and insulin, and remarkable improvement in glucose and insulin tolerance test profiles. Surprisingly, the expected HFD-induced metabolic endotoxaemia was also prevented by the ASOSAA treatment. CONCLUSIONS/INTERPRETATION: This study provides further evidence of the role of SAA in weight gain and insulin resistance. Moreover, we also suggest that beyond its proliferative and inflammatory effects, SAA is part of the lipopolysaccharide signalling pathway that links inflammation to obesity and insulin resistance.

New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice.

Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice.