The physiology and biochemistry of the Paleolithic Diet for weight reductionDavid C. Pendergrass, Ph.D.University of Kansas

Glycolysis to Lipogenesis

Sensory Neuron

monocyte

β- cell

Nociceptor

TRPV1 Hypothesis

TRPV1 – Physiological Mediator• Nociception• Inflammation• Infection• Immunity: Exposure to TRPV1 agonists• Keratinocytes PGE2 & IL-8• PBMC apoptosis

• Alimentary tract:• Metabolism• Hair growth regulation • Cancer development

• Reduced obesity• Smooth muscle cell regulation• Anorexigenic signaling

TRPV1 - • Agonists• Thermosensing >43C; pain• Protons (pH < 5.2)• Capsaicin• Depolarizing voltage > + 60 mv (outwardly rectifying)• Stretch

TRPV1 -• Sensitizing molecules

• 17-β-estradiol• Anandamide• Olvanil• Omega-3 polyunsaturated FA• 12-hydroperoxyeicosatetranoic acid (12-HPETE)• N-arachidonyl dopamine (NADA)• 2-aminoethoxydiphenyl borate (2-APB)• Inflammatory mediators

• Growth factors• Neurotransmitters: bradykinin, serotonin, histamine, prostaglandins• Peptides and small proteins• Lipids• Chemokines• Cytokines

• Intracellular phosphorylation• PKC• PKA• Tyrosine receptors kinases • Ca2+/CAM Kinase

TRPV1• Desensitizing molecules• PIP2

Sing-a-long

• If you’re healthy and you know it:

• If you’re healthy and you know it, Modern People gotta show it, if you’re healthy and you know it:

• Eat GOOD meat• Don’t eat wheat• Eat GOOD fish• Make the switch• Eat your greens• Buy new jeans

Bibliography• • Ahren, B. and M. Pettersson. "Calcitonin Gene-Related Peptide (Cgrp) and Amylin and the Endocrine Pancreas." Int J Pancreatol 6, no. 1 (1990): 1-15.• • Akiba, Y., S. Kato, K. Katsube, M. Nakamura, K. Takeuchi, H. Ishii and T. Hibi. "Transient Receptor Potential Vanilloid Subfamily 1 Expressed in Pancreatic Islet Beta Cells Modulates Insulin Secretion in Rats." Biochem Biophys Res Commun 321, no. 1 (2004): 219-25.• • Burcelin, R., W. Dolci and B. Thorens. "Glucose Sensing by the Hepatoportal Sensor Is Glut2-Dependent: In Vivo Analysis in Glut2-Null Mice." Diabetes 49, no. 10 (2000): 1643-8.• • Gao, H., K. Miyata, M. D. Bhaskaran, A. V. Derbenev and A. Zsombok. "Transient Receptor Potential Vanilloid Type 1-Dependent Regulation of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus Diminished in the Type 1 Diabetic Mouse." Diabetes 61, no. 6 (2012): 1381-90.• • Gonzalez, J. A., F. Reimann and D. Burdakov. "Dissociation between Sensing and Metabolism of Glucose in Sugar Sensing Neurones." J Physiol 587, no. Pt 1 (2009): 41-8.• • Gram, D. X., B. Ahren, I. Nagy, U. B. Olsen, C. L. Brand, F. Sundler, R. Tabanera, O. Svendsen, R. D. Carr, P. Santha, N. Wierup and A. J. Hansen. "Capsaicin-Sensitive Sensory Fibers in the Islets of Langerhans Contribute to Defective Insulin Secretion in Zucker Diabetic Rat, an Animal Model for Some Aspects

of Human Type 2 Diabetes." Eur J Neurosci 25, no. 1 (2007): 213-23.• • Guillot, E., A. Coste and I. Angel. "Involvement of Capsaicin-Sensitive Nerves in the Regulation of Glucose Tolerance in Diabetic Rats." Life Sci 59, no. 12 (1996): 969-77.• • Hu, S. S., H. B. Bradshaw, V. M. Benton, J. S. Chen, S. M. Huang, A. Minassi, T. Bisogno, K. Masuda, B. Tan, R. Roskoski, Jr., B. F. Cravatt, V. Di Marzo and J. M. Walker. "The Biosynthesis of N-Arachidonoyl Dopamine (Nada), a Putative Endocannabinoid and Endovanilloid, Via Conjugation of Arachidonic Acid

with Dopamine." Prostaglandins Leukot Essent Fatty Acids 81, no. 4 (2009): 291-301.• • Karlsson, S., A. J. Scheurink, A. B. Steffens and B. Ahren. "Involvement of Capsaicin-Sensitive Nerves in Regulation of Insulin Secretion and Glucose Tolerance in Conscious Mice." Am J Physiol 267, no. 4 Pt 2 (1994): R1071-7.• • Kreutter, D. K., S. J. Orena, A. J. Torchia, L. G. Contillo, G. C. Andrews and R. W. Stevenson. "Amylin and Cgrp Induce Insulin Resistance Via a Receptor Distinct from Camp-Coupled Cgrp Receptor." Am J Physiol 264, no. 4 Pt 1 (1993): E606-13.• • Noble, M. D., J. Romac, Y. Wang, J. Hsu, J. E. Humphrey and R. A. Liddle. "Local Disruption of the Celiac Ganglion Inhibits Substance P Release and Ameliorates Caerulein-Induced Pancreatitis in Rats." Am J Physiol Gastrointest Liver Physiol 291, no. 1 (2006): G128-34.• • Pettersson, M. and B. Ahren. "Insulin and Glucagon Secretion in Rats: Effects of Calcitonin Gene-Related Peptide." Regul Pept 23, no. 1 (1988): 37-50.• • Pettersson, M. and B. Ahren. "Calcitonin Gene-Related Peptide Inhibits Insulin Secretion Studies on Ion Fluxes and Cyclic Amp in Isolated Rat Islets." Diabetes Res 15, no. 1 (1990): 9-14.• • Pettersson, M., B. Ahren, G. Bottcher and F. Sundler. "Calcitonin Gene-Related Peptide: Occurrence in Pancreatic Islets in the Mouse and the Rat and Inhibition of Insulin Secretion in the Mouse." Endocrinology 119, no. 2 (1986): 865-9.• • Pettersson, M., I. Lundquist and B. Ahren. "Neuropeptide Y and Calcitonin Gene-Related Peptide: Effects on Glucagon and Insulin Secretion in the Mouse." Endocr Res 13, no. 4 (1987): 407-17.• • Sangiao-Alvarellos, S. and F. Cordido. "Effect of Ghrelin on Glucose-Insulin Homeostasis: Therapeutic Implications." Int J Pept 2010, (2010).• • Suri, A. and A. Szallasi. "The Emerging Role of Trpv1 in Diabetes and Obesity." Trends Pharmacol Sci 29, no. 1 (2008): 29-36.• • Thorens, B. "Brain Glucose Sensing and Neural Regulation of Insulin and Glucagon Secretion." Diabetes Obes Metab 13 Suppl 1, (2011): 82-8.• • Thorens, B. "Sensing of Glucose in the Brain." Handb Exp Pharmacol, no. 209 (2012): 277-94.• • Tsui, H., G. Paltser, Y. Chan, R. Dorfman and H. M. Dosch. "'Sensing' the Link between Type 1 and Type 2 Diabetes." Diabetes Metab Res Rev 27, no. 8 (2011): 913-8.• • Van Buren, J. J., S. Bhat, R. Rotello, M. E. Pauza and L. S. Premkumar. "Sensitization and Translocation of Trpv1 by Insulin and Igf-I." Mol Pain 1, (2005): 17.• • Weller, K., P. W. Reeh and S. K. Sauer. "Trpv1, Trpa1, and Cb1 in the Isolated Vagus Nerve--Axonal Chemosensitivity and Control of Neuropeptide Release." Neuropeptides 45, no. 6 (2011): 391-400.• • Winter, Z., A. Buhala, F. Otvos, K. Josvay, C. Vizler, G. Dombi, G. Szakonyi and Z. Olah. "Functionally Important Amino Acid Residues in the Transient Receptor Potential Vanilloid 1 (Trpv1) Ion Channel - an Overview of the Current Mutational Data." Mol Pain 9, no. 1 (2013): 30.• • Zhang, Z., C. S. Winborn, B. Marquez de Prado and A. F. Russo. "Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion." J Neurosci 27, no. 10 (2007): 2693-703.• • Zsombok, A. "Vanilloid Receptors--Do They Have a Role in Whole Body Metabolism? Evidence from Trpv1." J Diabetes Complications 27, no. 3 (2013): 287-92.• • Zsombok, A., H. Gao, K. Miyata, A. Issa and A. V. Derbenev. "Immunohistochemical Localization of Transient Receptor Potential Vanilloid Type 1 and Insulin Receptor Substrate 2 and Their Co-Localization with Liver-Related Neurons in the Hypothalamus and Brainstem." Brain Res 1398, (2011): 30-9.• •