br Materials and methods br Results br
Materials and methods
Discussion To understand the molecular basis for how ghrelin secretion is regulated at the cellular level, we identified the full repertoire of 7TM receptors and G proteins in gastric ghrelin vitamin d receptor and functionally characterized the majority of the receptors which were highly enriched, highly expressed and/or previously-implicated in the control of ghrelin secretion. Thus a comprehensive picture is presented of the G protein-coupled receptor signaling machinery controlling hormone secretion directly at the ghrelin cell (Figure 8).
Conclusions and perspectives A rather comprehensive picture is presented of the repertoire of 7TM receptors for neurotransmitters, neuropeptides, hormones, paracrine lipid messengers and in particular metabolites, and the corresponding Gα subunits that are expressed and functionally control ghrelin secretion directly at the level of the ghrelin cell (Figure 8B). This provides a new and significantly expanded basis for understanding the physiology of the cell producing the important orexigenic-glucoregulatory hormone ghrelin and thereby an expanded basis for selecting targets and developing novel therapeutic agents to control ghrelin secretion. The observation that certain receptors inhibit ghrelin secretion while stimulating secretion in other endocrine cell types and the differential expression of certain G protein α-subunits, which possibly could explain this difference in signaling, could open for a knowledge-based discovery process for signaling biased and tissue selective pharmaceuticals in general.
Conflict of interest
Acknowledgments We are grateful for the expert technical assistance from Susanne Hummelgaard. The Novo Nordisk Foundation Center for Basic Metabolic Research (http://www.metabol.ku.dk) is supported by an unconditional grant from the Novo Nordisk Foundation to University of Copenhagen. The project was also supported by the UNIK project for Food, Fitness & Pharma (http://www.foodfitnesspharma.ku.dk) from the Danish Ministry of Science, Technology and Innovation. T.W.S and K.L.E were further supported by grants from the Lundbeck Foundation and from the Danish Medical Research Council. M.S.E was supported by a PhD scholarship from the Faculty of Health and Medical Sciences, University of Copenhagen. P.K.P. received funding from the Endocrine Fellows Foundation. A.K.W. was supported by NIH (T32DA7290). K.A. was supported by an EMBO long-term fellowship.
Is Lactate Only Metabolic Junk? Lactate is largely produced within the tumour microenvironment (TME; see Glossary) by cells exploiting aerobic glycolysis (Warburg metabolism). Otto Warburg was indeed one of the first scientists to identify lactate as a characteristic product released by tumour cells, and proposed a clear correlation between the biosynthesis of lactate (‘lactagenesis’), including under aerobic conditions and carcinogenesis. This view has not changed, although the perspective has now been enlarged to include several cellular sources of lactate, and the effects of secreted lactate embrace not only carcinogenesis but also tumour malignancy. Warburg-dependent cells possess an ‘inefficient’ mechanism for producing ATP, favouring aerobic glycolysis and lactate production in the cytosol instead of exploiting glucose oxidation through mitochondrial oxidative phosphorylation (OXPHOS). The advantage of such deregulated energetics is to favour the accumulation of glycolytic intermediates, fuelling derivative anabolic pathways, such as the pentose phosphate pathway, the hexosamine pathway, and amino acid synthesis, thereby sustaining cell proliferation . However, recent advances have highlighted substantial intratumoural metabolic heterogeneity, depending on the tissue context and TME, that regulates the metabolic strategies in tumour cells, leading, for example, to concurrent glycolysis and glucose oxidation in the same tissue . Nevertheless, the majority of cancer cells enhance glucose and glutamine consumption to satisfy their requirements for rapid proliferation. In aerobic glycolytic tumour cells, glucose is partially oxidized into pyruvate which is subsequently reduced to lactate, that is then extruded into the extracellular space. In addition, glutamine can fuel the tricarboxylic acid (TCA) cycle by providing several advantages to cancer cells, particularly in a metabolically restricted environment (i.e., hypoxia, low glucose). Glutamine supports lipid synthesis through reductive carboxylation , and promotes glutathione synthesis and NADPH production via conversion of malate into pyruvate through malic enzyme activation (thus presumably contributing to lactate production) to improve their antioxidant defenses .