Speaker:Chung-Han Wang. introduction Obesity being one of the major issues of public health nowadays, with more than 500 million obese adults worldwide.

Slides:



Advertisements
Similar presentations
Endocrine Control Chapter 32.
Advertisements

Regulation of food intake. Food intake Regulation –Endocrine Adipose tissue Pancreas Liver Muscle –CNS.
1 Chapter 9 Motivation: Hunger. 2 Internal Regulatory Systems Usually Work, But… The percentage of obese Americans jumped from 12% in 1991 to 21% in 2001.
GHRELIN SIGNALING PATHWAY - SHRADDHA D. REGE. Ghrelin  Is a 28 amino acid Orexigenic peptide and hormone.  Neuroendocrine hormone – exerts numerous.
Leptin signalling.
BIOCHEMISTRY OF LEPTIN Shalini Jain and Hariom Yadav Animal Biochemistry Division Natioanal Dairy Research Institute Karnal (Haryana), India.
Disease X in 1985 No Data
Homeostatic Control of Metabolism
Molecular Mechanism of Metabolic disorders Shinichi Oka, PhD Department of Cell Biology and Molecular Medicine Rutgers New Jersey Medical School MSB-I543.
IGF in circulation The majority (> 75 %) exists as bound form –IGF binding proteins (IGFBPs) IGFBPs –6 proteins and several related proteins –Serum IGFBP.
Anticancer Therapy: Kinase Inhibitors Charles Harrell.
Endocrine Block | 1 Lecture | Dr. Usman Ghani
Endocrine System. I. Endocrine system A. Endocrine tissues & organs are found throughout the body some along organs part of other systems others found.
Weight Management Energy Balance Equation Balance: energy intake = energy expenditure energy intake > energy expenditure = weight gain energy intake.
Obesity Dr. Sumbul Fatma. Obesity A disorder of body weight regulatory systems Causes accumulation of excess body fat >20% of normal body weight Obesity.
Chapter 45 Hormones and the Endocrine System. The Body’s Long-Distance Regulators The Body’s Long-Distance Regulators An animal hormone An animal hormone.
Fat Overweight HDL Diabetes Hypertension Depression Caloric value BMI Overeating Insulin Resistance.
1 Chapter 9 Motivation. 2 Internal Regulatory Systems Usually Work, But… The percentage of obese Americans jumped from 12% in 1991 to 21% in At.
Signal Response and Amplification
Functional interactions between calmodulin and estrogen receptor-α
Biomembrane and Cell signalling BCH 452(V) Cell To Cell Comunication Dr. Samina Hyder Haq Assistant professor Dept of biochemistry Collage of Science King.
BASIC PHARMACOLOGY 2 SAMUEL AGUAZIM(MD).
The Road To Metabolic syndrome
Obesity Dr. Sumbul Fatma. Obesity A disorder of body weight regulatory systems Causes accumulation of excess body fat >20% of normal body weight Obesity.
به نام خدا.
Group Red – Demacia Gabe, Chris, Tom. - Enzymes with more than one polypeptide chain can change between an active shape and an inactive shape - When the.
Genes that regulate appetite. Wisse, BE. and Schwartz, MW. The skinny on neurotrophins. Commentary on: Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones.
瘦體素 Obesity and Leptin WT ob (db) 2010 Albert Lasker award
By Jaymathi Dhanapal.  Obesity is a major health epidemic as obesity raises the risk for many chronic and potentially life-threatening illnesses, including.
The physiological and pathophysiological roles of the Urocortins Krisztina Kárpáti and Hélène Rivière JPEMS
Leptin Signaling Pathway Part 1. Leptin: The Beginning Identified by Jeffrey Friedman in Circulating peptide hormone secreted almost exclusively.
AH BIOLOGY COMMUNICATION WITHIN MULTICELLULAR ORGANISMS.
Endocrine system. General Infomation Connected to the nervous system via the Hypothalamus. Often in this system, the sensor and control center are the.
Negative regulation of cell cycle by intracellular signals Checkpoint p53 detects DNA damage & activates p21 p21 inhibits cdk2-cyclinA Intracellular Regulation.
Transduction of Extracellular Signals Specific receptors in plasma membranes respond to external chemicals (ligands) that cannot cross the membrane: hormones,
Intracellular Signal Transduction Pathways and Cascades.
Feeding Pathways. Hunger vs. Satiety Neuroscience (Bears, Connors, Paradiso) Controlled by communication between the gut and parasympathetic nervous system.
Human Nutrition Activity: Nutrient and calorie log.
Maintaining Good Health Page 467. Four things to do to keep yourself healthy: 1.Eat a balanced diet. 2.Keep your weight within the healthy range for you.
In the name of God.
1 Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis Min-Seon Kim1,6, Youngmi K Pak2,6, Pil-Geum Jang2,6, Cherl Namkoong2,
Leptin: Food intake, Energy balance, and Endocrine Function By: Dina M, Trabzuni Advisor; Prof. Hamza Abu-Tarboush 698 FSN.
Protein Receptors & Signal Transduction
Energy Balance and Body Composition Lancelot McLean, PhD.
Immune Receptors and Signal Transduction
Hormones and the Endocrine system
Leptin Hormone and Appetite Control
Obesity Dr. Sumbul Fatma.
BACE1 Knockout Mice and BACE1 inhibition in Mouse models of obesity/diabetes Stuart Irvine.
Leptin receptor functions: When leptin binds to its receptor (LEPR-B) the receptor undergoes a conformational change that activates the receptor-associated.
Ch. 32 Warm-Up What type of behavior in animals might be triggered by cold temperatures? What type of behaviors might be triggered in hot temperatures?
6.6 – Hormones, homeostasis and reproduction
Communication within Multicellular Organisms
6.6 – Hormones, homeostasis and reproduction
Cell to Cell Communication via Enzyme Linked Receptors
Ch. 32 Warm-Up What type of behavior in animals might be triggered by cold temperatures? What type of behaviors might be triggered in hot temperatures?
Michael K. Badman, Jeffrey S. Flier  Gastroenterology 
The paradox of neuronal insulin action and resistance in the development of aging- associated diseases  Sophie M. Steculorum, Maite Solas, Jens C. Brüning 
LEP: The Leptin Gene and Its Correlation to Obesity
Obesity and the Regulation of Energy Balance
Selective Insulin and Leptin Resistance in Metabolic Disorders
Figure 1 Physiological functions of leptin and ghrelin
Volume 18, Issue 1, Pages (July 2013)
AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism  Barbara B. Kahn, Thierry Alquier, David Carling,
Michael K. Badman, Jeffrey S. Flier  Gastroenterology 
Unit 1 Cells and Proteins Advanced Higher Biology Miss Aitken
Hormones and the Endocrine System
6.6 Hormones and homeostasis
Ch. 32 Warm-Up What type of behavior in animals might be triggered by cold temperatures? What type of behaviors might be triggered in hot temperatures?
6.6 – Hormones, homeostasis and reproduction
Presentation transcript:

Speaker:Chung-Han Wang

introduction Obesity being one of the major issues of public health nowadays, with more than 500 million obese adults worldwide in Obesity is a chronic disease, which originates from a myriad of causes leading to a steady imbalance between energy intake and energy expenditure -fat mass has been correlated to higher risk of developing severe diseases such as type 2 diabetes, cardiovascular disease, and cancers.

A pharmacological drug against obesity must result- 1.food intake 2.increase in energy expenditure The discovery of leptin in 1994 raised the possibility of new therapeutic strategies to combat obesity epidemic. Recombinant leptin to obese rodents and humans with congenital leptin deficiency significantly decreases body weight and food intake.

leptin therapy for patients with very low leptin or leptin deficiency has proven to be relevant for diseases such as lipoatrophy, anorexia nervosa, hypothalamic amenorrhea, and some neuroendocrine disturbances. Recombinant leptin monotherapy is totally inefficient in decreasing body weight of diet-induced obese (DIO) mice as well as obese humans who are not leptin- deficient but rather hyperleptinemic, associated with a loss of responsiveness to leptin. These observations led to the concept of so-called “leptin resistance.”

Few words on leptin and the leptin receptor Leptin, a peptidic hormone mainly secreted by white adipose tissue, is essential in the control of energy homeostasis-food intake and energy expenditure-binding of leptin to its receptor OBR, a type I cytokine receptor. Several isoforms of OBR have been described as a result of alternative mRNA splicing leading to several short isoforms (OBRa, OBRc, OBRd, and OBRf), one long isoform OBRb with a long cytosolic C-terminus tail and one soluble isoform OBRe.

OBRb expression is more restricted with high levels in hypothalamic nuclei such as the arcuate nucleus (ARC)-in the development of leptin resistance. Accordingly, exposure of rodents to a high-fat diet rapidly decreases the phosphorylation of STAT3 in the ARC or the ventral tegmental area (VTA), while leptin-sensitivity is simultaneously maintained in some other hypothalamic nuclei.

OBRb is able to trigger various signal transduction pathways OBRb is the main isoform responsible for the effect of leptin on body weight control. Activation of the Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway leads to an increase of anorexigenic signals and a decrease of orexigenic signals. Leptin is also able to activate the insulin receptor substrate (IRS)/phosphatidylinositide 3-kinase (PI3K) pathway, essential for the regulation of glucose homeostasis. leptin inhibits in the brain the energy sensor, adenosine monophosphate-activated protein kinase (AMPK), to decrease eating. The activation of extracellular signal-regulated kinase (ERK) is another pathway mediating the anorectic action of leptin in the hypothalamus.

Leptin binding to its receptor OBR is the first event triggering conformational change and eventual oligomerization of OBR, both necessary for receptor activation and subsequent signal transduction

OBR structure CRH2 and Ig leptin binding and receptor activation. N-terminal region CRH1: cytokine receptor homologous domain Ig: Immunoglobulin FNIII: two fibronectin type 3 TM: transmembrane region

Leptin and OBR binding structure Binding site I: poorly defined Binding site II: high affinity interaction leptin and the OBR CRH2 domain Binding site III: 1.conformational changes 2.activation of OBR Ig domain leptin mutations at site I (L39A/D40A/F41A) and III (S120A/T121A) become antagonists.

leptin gene -ob/ob mice leptin receptor gene-db/db mice, fa/fa rats A409E and R612H on human OBR lead to severe obesity in patients possibly by impairing binding site III and binding site II. macronutrients fat and sugar are detrimental to leptin sensitivity-leptin resistance is not yet completely understood.

Potential therapeutic targets for the prevention or reversal of leptin resistance 1.increase of leptin signaling with new OBR agonists 2. decrease of the inhibitory function of OBR negative regulators(SOCS3, PTP1B) 3. Increase of leptin transport across the blood–brain barrier or median eminence 4. increase of OBR cell surface expression by enhancing OBR anterograde traffic and recycling or by decreasing OBR constitutive internalization and lysosomal degradation (endospanin 1-dependent pathways) 5. decrease of ER stress