Neuroendocrinology an integrative approach

Transcription

1 Neuroendocrinology an integrative approach JP Advis DVM, Ph.D. Bartlett Hall, Animal ciences, Cook, (848) , 06 Course website: rci.rutgers.edu/~advis Material to be covered: Meeting 01: Introduction to Neuroendocrinology (1) Meetings 02-03: How to answer and present home-works #01-#02 (2) Meetings 04-06: How to answer and present home-works #03-#06 Meetings 07-08: RVIW AND TT #1 (draft overview of home-works #03-#06) Meeting 09: tress as a Neuroendocrine alarm sensor (1) Meetings 10-12: Neuroendocrine Control of Reproduction (3) Meeting 13: tress and the Neuroendocrine Control of Reproduction (1) Meetings 14-15: RVIW AND TT #2 (draft answers of home-works #03-#04) Meetings 16-17: Neuroendocrine Control of Hydro-mineral Homeostasis (2) Meetings 18-19: Neuroendocrine Control of Food Intake and Metabolism (2) Meetings 20-21: Neuroendocrine Control of Biological Rhythms (2) Meetings 22-23: RVIW AND TT #3 (draft answers of home-works #05-#06) Meetings 24-27: tudent oral presentations of their two best home-works (4) Meetings 28-29: RVIW AND TT #4 (final answers of home-works #03-#06) 01 Introduction to Neuroendocrinology (1) How to answer and present home-works #01-#02 (2) The circle and this course home-works (3) RVIW AND TT #1 (draft overview of home-works #03-#06) 09 tress as a Neuroendocrine alarm sensor (1) Neuroendocrine Control of Reproduction (3) 13 tress and the Neuroendocrine Control of Reproduction (1) RVIW AND TT #2 (draft answers of home-works #03-#04) Neuroendocrine Control of Hydro-mineral Homeostasis (2) Neuroendocrine Control of Food Intake and Metabolism (2) Neuroendocrine Control of Biological Rhythms (2) RVIW AND TT #3 (draft answers of home-works #05-#06) tudent oral presentations of their two best home-works (4) RVIW AND TT #4 (final answers of home-works #03-#06) Page 1

2 Introducing the circle (part #3) LCTUR #04 LCTUR #05 LCTUR #06 From a working refrigerator, to a theoretical control system, to a homework, an abstract and an oral presentation to a brain CRH integrator, to maintaining homeostasis to hypothalamic integrators, to endocrine and neuronal afferent / efferent pathways to a brain TRH integrator, to potential energy and the capability to do work to a brain GnRH integrator, to female cyclic reproduction From hydro-mineral signals, to brain-related integrators to cardiovascular, respiratory, and renal function Introducing the circle (part #3) LCTUR #06 Today s lecture 06 Page 2

3 Introducing the circle (part #3) LCTUR #06 ( Neuronal = N Blood - Born = BB ) BB BB Hypothalamic nuclei / areas PVN, paraventricular nucleus ARC, arcuate nucleus VMH, ventro-medial nucleus DMH, dorso-medial nucleus LH, lateral hypothalamus M, median eminence xtra-hypothalamic nuclei / areas A, amigdala BB AP, area postrema DMN, dorso motor nucleus of vagus NT, nucleus tractus solitarious PBN, para braquial nucleus MFB, medial forebrain bundle N DMH VMH PVN ARC M A PBN AP LH DMN The PVN is a main integrator site for thermoregulation, energy metabolism and food intake! NT Introducing the circle (part #3) LCTUR #06 Glucose availability glucose sensitive neurons in brain stem (NT, AP), hypothalamus (VMH-DMH, PVN) and hepato-portal circulation (to NT). ensory stimulation to NT, PBN and cortex. Body energy stores leptin in ARC-VMH The PVN is a main integrator site for thermoregulation, energy metabolism and food intake! Page 3

4 Introducing the circle (part #3) LCTUR #06 hort - term inputs to PVN Glucose, Proteins and Fats GI volume and GI peptides Long - term inputs to PVN Insulin and Leptin Glucocorticoids, Thyroid and GH / IGF1 The PVN is a main integrator site for thermoregulation, energy metabolism and food intake! Introducing the circle (part #3) LCTUR #06 (e.g.) Leptin (e.g.) Leptin inhibits food intake Catecholamines erotonin Histamine GABA NPY and Galanin CRH and CCK amh, AGRP and GLP1 Orexins and MCH CART ßND, amh, CART, CRH stimulate inhibit NPY, AGRP, MCH, Orexin Na + (NT-PVN) ; DA - (LH-PVN) 5HT1b - (LH-PVN) H2 - (VMH-PVN) GABAa + (VMH) and - (LH) NPY + ; GAL + (ARC-PVN) CRH - (A-VMH) ; CCK - (NT-PVN) amh - ; AGRP + (ARC-PVN-MC4R) GLP1 - (NT-PVN) Orexin + ; MCH + (LH-PVN) CART - (ARC-DMH, NT) Main central pathways regulating food intake! Page 4

5 Introducing the circle (part #3) LCTUR #06 Jolie-Amado Aurelie et al (2014). The hypothalamic arcuate nucleus and the control of peripheral substrates. Best Practice & Research Clinical ndocrinology & Metabolism 28: ARC & nutrient partitioning of a mouse brain showing nuclei engaged in energy balance. ARC neurons project to 2 nd order targets including the PVN, HyLat, PBN, DA neurons in midbrain VTA and NT. Hypothalamic nuclei also receive input from DMX. The PVN integrates inputs from ARC neurons and from Ch. The ARC contains at least two populations of neurons that control energy balance the orexigenic/anabolic neurons producing NPY and AgRP-related protein and the anorexic/ catabolic neurons producing POMC and the natural ligand for the melanocortin receptor. These first order neurons are located exquisitely close to the M, a circumventricular organ that lies at the bottom of the 3rdV. The M represents a microenvironment composed of fenestrated capillaries (red) and glia cells highly structured by tight junctions (green). Together, this creates a privileged region of the BBB in which macro-molecules and energy-related (leptin, insulin, ghrelin) peptides access target neurons in the ARC through a regulated passage involving highly specialized hypothalamic glial cells: the tanycytes. ARC neurons are of diverse nature and display segregated projection to hypothalamic and extra hypothalamic nuclei. Integration of Ch Clock input and ARC-relayed nutrient input results in AN-mediated coordination of peripheral organ activity. This process can be independent from the regulation feeding, neuroendocrine release or metabolic rate and results in the concerted orchestration of nutrient transformation, storage and utilization. Introducing the circle (part #3) LCTUR #06 An overview of neural circuitry controlling both appetitive & hedonic aspects of food intake is shown. xcitatory synaptic inputs are indicated by arrowheads, and inhibitory inputs are indicated by bars Lee Daniel and Blackshaw (2014). Feed Your Head: N Neurodevelopmental Control of Feeding and Metabolism. Annu Rev Physiol. 76: Page 5

6 Introducing the circle (part #3) LCTUR #06 Gautron Laurent et al (2014). Neural Control of nergy Balance: Translating Circuits to Therapies. Cell 161: Introducing the circle (part #3) LCTUR #06 Gautron Laurent et al (2014). Neural Control of nergy Balance: Translating Circuits to Therapies. Cell 161: Page 6

7 Introducing the circle (part #3) LCTUR #06 Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent findings in the area of sympathetic control of TG metabolism. Various neuronal populations, such as neuropeptide Y (NPY)-expressing neurons and melanocortin-expressing neurons, as well as peripherally produced hormones (i.e., GLP-1, leptin, and insulin), modulate sympathetic outflow from the hypothalamus toward target organs and thereby influence peripheral TG metabolism. We conclude that sympathetic stimulation in general increases lipolysis in WAT, enhances VLDL-TG production by the liver, and increases the activity of BAT with respect to lipolysis of TG, followed by combustion of fatty acids toward heat. Moreover, the increased knowledge about the involvement of the neuroendocrine system in TG metabolism presented in this review offers new therapeutic options to fight hypertriglyceridemia by specifically modulating sympathetic nervous system outflow toward liver, BAT, or WAT. Geerling Janine et al n (2014). ympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies. J Lipid Res. 55(2): Introducing the circle (part #3) LCTUR #06 Parker Helen et al (2014). The role of gut endocrine cells in control of metabolism and appetite. xp Physiol 99.9: After food is ingested, nutrients pass through the gastrointestinal tract, stimulating the release of a range of peptide hormones. Among their many local, central and peripheral actions, these hormones act to mediate glucose metabolism and satiety. Indeed, it is the modification of gut hormone secretion that is considered partly responsible for the normalization of glycaemic control and the reduction in appetite seen in many patients after certain forms of bariatric surgery. This review describes recent developments in our understanding of the secretion and action of anorexigenic gut hormones, primarily concentrating on glucagon-like peptide-1 (GLP-1). GLP-1-based therapies are effective treatments for type 2 diabetes, and mimetics of GLP-1 are under evaluation as anti-obesity agents. As well as having glucose-lowering effects mediated by the pancreas, benefits include weight loss and slowed gastric emptying. Many of the reported actions of GLP-1 are not fully understood, but recent confirmation of the expression of glp1r in pancreatic islet cells and the peripheral and central nervous system will aid the clarification of GLP-1 physiology and pharmacology. The enhancement of endogenous GLP-1 release to treat diabetes is an alternative therapeutic strategy currently under investigation. As enteroendocrine cells are now recognized to express a spectrum of hormonal mediators, targeting the gut endocrine system could release a soup of metabolically active hormones with anorexigenic as well as incretin effects and mimic some of the physiological responses to gastric bypass surgery. Analyses of isolated enteroendocrine cell populations have identified sensory pathways that might be suitable for pharmacological targeting. Further insights into the GLP-1-secreting enteroendocrine cell population and GLP1R expression and signalling will allow us to exploit the properties of this gut hormone to the fullest. Page 7

8 Introducing the circle (part #3) LCTUR #06 Bailey M et al (2014). Circadian regulation of metabolism. J. ndocrinol; 222(2), R75 R96. Introducing the circle (part #3) LCTUR #06 Tolson KP and Chappell P (2012). The changes that are a-timed: metabolism, endogenous clocks, and the timing of puberty. Frontiers in ndocrinology volume 3 article 45. Page 8

9 Introducing the circle (part #3) LCTUR #06 Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent findings in the area of sympathetic control of TG metabolism. Various neuronal populations, such as neuropeptide Y (NPY)-expressing neurons and melanocortinexpressing neurons, as well as peripherally produced hormones (i.e., GLP-1, leptin, and insulin), modulate sympathetic outflow from the hypothalamus toward target organs and thereby influence peripheral TG metabolism. We conclude that sympathetic stimulation in general increases lipolysis in WAT, enhances VLDL-TG production by the liver, and increases the activity of BAT with respect to lipolysis of TG, followed by combustion of fatty acids toward heat. Moreover, the increased knowledge about the involvement of the neuroendocrine system in TG metabolism presented in this review offers new therapeutic options to fight hypertriglyceridemia by specifically modulating sympathetic nervous system outflow toward liver, BAT, or WAT. Geerling JJ et al (2014) ympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies. J Lipid Res Feb; 55(2): Introducing the circle (part #3) LCTUR #06 Test #3 Test #2 Final Homework ub-questions a through f Paper Presentation Intro, M&M, results, discussion Test #1 Abstract Intro, THM, lines of evidence, THM Oral Presentation THM, objective, results, THM, discussion Page 9

10 Info from prerequisite material -appendix slides- The following slides come from the Integrative Physiology and ystem physiology courses thought by this instructor (JP Advis). They are presented here as a way to help students review basic prerequisite information. They have been organized by main topics and subtopics, and are included as appendix to most lectures. These prerequisite material will not be presented in the lectures for this Neuroendocrinology course, except for discussion purposes. APPNDIX #06 The Knee Jerk Reflex and the circle concept Page 10

11 APPNDIX #06 theoretical components! of a feedback! (e.g. the refrigerator )!??? APPNDIX #06 theoretical components! of a feedback! (e.g. the refrigerator )! variable under control (t F/C)! thermostat (set point)! t F/C detector (feedback)! comparator (integrator)! common language! error signal (on/off)! and engine! feedback detector T!! M! P!! R! A! T! U! R!! negative feedback loop set - point comparator error signal engine controlled variable! L!! C! T! R! I! C! A! L!!! I! G! N! A! L!! Page 11

12 APPNDIX #06 theoretical components! of a feedback! (e.g. the refrigerator )! variable under control (t F/C)! thermostat (set point)! t F/C detector (feedback)! comparator (integrator)! common language! error signal (on/off)! and engine! set point APPNDIX #06 Questions to be asked about any homeostatic reflex or of the circle as a thinking process Page 12

13 APPNDIX #06 ome important generalizations about homeostatic control or of the circle as a thinking process APPNDIX #06 xamples of an homeostatic control and a driving behavior that can be considered as circles Page 13

14 APPNDIX #06 xample of an homeostatic control that can be considered as a circle APPNDIX #06 xample of how an homeostatic control considered as a circle can be modified by higher regulators -Fb Page 14

15 APPNDIX #06 xample of how an homeostatic control considered as a circle can be modified by higher regulators set point APPNDIX #06 set point Page 15

16 set point afferent story line integrator center a reflex arc a base for a control model efferent story line diagram for a control system as that present in a refrigerator sensor negative feedback story line effector if story lines are linked through an integrator and a -Fb, then you have control APPNDIX #06 Page 16

17 C C C Neuroendocrine Transducer Cells (NTC). 2 P4 receptor GnRH Cortisol. receptor CRH T3 receptor TRH gonadal hierarchy AP adrenal hierarchy AP thyroid hierarchy AP gonad adrenal thyroid 2, P4 cortisol T3 / T4 APPNDIX #06 reproduction growth and development neuroendocrine control maintenance of the internal environment energy harvesting utilization storage Page 17

18 APPNDIX #06 et point input Insulin & glucagon & GRH GI neuroendocrine control of glycemia et point input Cortisol & pinephrine T3 & Leptin other systems and / or higher control centers APPNDIX #06 Questions to be asked about any homeostatic reflex or of the circle as a thinking process Page 18

19 APPNDIX #06 tudents will be introduce and learn to use the circle concept, as a way of, in a progressive way. Your first six homework deal with single circle problems, while the last three homework are related to two or even to several circles operating simultaneously. The way to assess multiple circles is to tackle them two at a time and transform these two circles into one. All students at some time have been confronted when studying to material that looks like a fog. This usually happen when you do not understand the topic and are unable to get a handle even into a little piece that could make sense. The circle approach helps in separating elements in the foggy environment to get started. Without knowing it, you might have used this approach when preparing your application to a job, or even to a university program. It is also used as a clinical approach for human and veterinary medicine. APPNDIX #06 Please notice that the required answers to your homework questions are nothing else that a deconvolution of elements forming a circle. Read your homework questions having the circle idea in your head. When you are tackling each of the sub-questions guiding your answers (a,b1,b2,b3,c1,c2,c3,d1,d2,d3,e1,e2,e3) keep in your mind that they are all circle related. When you first attempt to answer your homework questions, just write everything you know about the topic. Then come the most important aspect of studying, which is DITING. If you understand the topic, you should be able to reduce all your answer for each sub-question, into a single sentence or two sentences. Keep in mind at all time that if you can not write it, you do not know the topic you are attempting to write about. I am aware that it is a long and difficult road, using the circle idea, but with time and practice you will notice you are doing it without even thinking about it, as you are studying. However, do not get ahead of yourself. Page 19