Elevated Non-Esterified Fatty Acid Concentrations during Bovine Oocyte Maturation Compromise Early Embryo Physiology

Elevated concentrations of serum non-esterified fatty acids (NEFA), associated with maternal disorders such as obesity and type II diabetes, alter the ovarian follicular micro-environment and have been associated with subfertility arising from reduced oocyte developmental competence. We have asked whether elevated NEFA concentrations during oocyte maturation affect the development and physiology of zygotes formed from such oocytes, using the cow as a model. The zygotes were grown to blastocysts, which were evaluated for their quality in terms of cell number, apoptosis, expression of key genes, amino acid turnover and oxidative metabolism. Oocyte maturation under elevated NEFA concentrations resulted in blastocysts with significantly lower cell number, increased apoptotic cell ratio and altered mRNA abundance of DNMT3A, IGF2R and SLC2A1. In addition, the blastocysts displayed reduced oxygen, pyruvate and glucose consumption, up-regulated lactate consumption and higher amino acid metabolism. These data indicate that exposure of maturing oocytes to elevated NEFA concentrations has a negative impact on fertility not only through a reduction in oocyte developmental capacity but through compromised early embryo quality, viability and metabolism

Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases

Saturated fatty acid metabolism is key link between cell division, cancer, and senescence in cellular and whole organism aging

Cellular senescence is an in vivo and in vitro phenomenon, accompanied by physiological changes including cessation of division and disturbances of organelle structure and function. Review of the literature was undertaken to determine whether there is evidence that whole organism aging and cell senescence share a common initiation pathway. In vivo aged cells of different lineages, including aged T lymphocytes, show high expression of the INK4A-p16 gene. In cell culture when telomeres are shortened past a key length or state, the Arf/Ink gene system (p16/p14 humans, p16/p19 mice) switches on and activates p53, which suppresses further cell division. The p53 gene is a key tumor suppressor and its deletion or mutation allows cancerous growth. The switching on of p53 also causes changes in fatty acid metabolism, especially down-regulation of both fatty acid synthase and stearoyl-CoA (delta-9) desaturase. The co-suppression of these genes together with enhanced uptake of extracellular fatty acids, leads to raised levels of cellular palmitate and induction of either apoptosis or senescence. In senescent cells, the fatty acid composition of the cellular membranes alters and leads to changes in both structure and function of organelles, especially mitochondria. Animal models of accelerated aging exhibit repression of stearoyl-CoA desaturase activity while anti-aging calorie restriction stimulates the same enzyme system. It is concluded that aging in cells and whole organisms share a common initiation pathway and that cellular senescence is protective against cancer. Healthy longevity is likely to be most enhanced by factors that actively suppress excessive cell division