Page 1 |
Save page Remove page | Previous | 1 of 122 | Next |
|
small (250x250 max)
medium (500x500 max)
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
Subset |
MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF CB1
ANTAGONISM IN CANINE MODEL OF OBESITY
by
Malini Subramanian Iyer
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2009
Copyright 2009 Malini Subramanian Iyer
Object Description
| Title | Molecular mechanisms underlying the effects of CB1 antagonism in canine model of obesity |
| Author | Iyer, Malini Subramanian |
| Author email | miyer@usc.edu; urfriendmalini@gmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2009-10-14 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-11-02 |
| Advisor (committee chair) | Tokes, Zoltan |
| Advisor (committee member) |
Bergman, Richard Hong, Young |
| Abstract | Obesity has become one of the major health problems all over the world with its co-morbities such as insulin resistance contributing to further complications of the disease. Recently, pharmacotherapeutic interventions exploring the Endocannabinoid System (ECS) have been in focus for combating obesity. One of the therapeutic interventions targeting the ECS is the cannabinoid receptor 1 (CB1) antagonist rimonabant (RIM). Recent physiological studies in our laboratory showed that in a high fat fed canine model, RIM reduces body weight and fat accumulation in visceral (VIS) and subcutaneous (SQ) depots along with improvement in insulin sensitivity.; The purpose of the first study was to investigate molecular effects of RIM on the morphology and functionality of adipocytes contributing to the physiological changes in the fat depot. Using univariate normal mixture decomposition, we demonstrated that in both VIS and SQ depots, RIM completely prevented the formation of large cells and essentially normalized cell size to pre-fat conditions. We also found that RIM reduced the gene expressions of transcription factors involved in adipogenesis and lipid accumulation namely, peroxisome proliferator activated protein (PPAR-γ) and sterol response element binding protein-1c (SREBP-1c), by 67% and 78.5% respectively in the VIS depot. RIM reduced expressions of enzymes involved in lipolysis namely, hormone sensitive lipase (HSL) and adipose tissue triglyceride lipase (ATGL) in the VIS depot. Reduced lipolysis upon RIM treatment can be attributed to its effect on improved insulin sensitivity. Another phenomenon associated with insulin-resistance is chronic low grade inflammation. Using real-time PCR technique, we found that RIM improved inflammation induced by fat-feeding by reducing the expression of pro-inflammatory cytokines namely, IL-6 and TNF-α by 3 fold and 7 fold, respectively. Most importantly, we found that RIM induced the expression of an insulin-sensitizing adipokine, adiponectin by 4 fold in the VIS depot and 2.5 fold in the SQ depot compared fat-feeding period. Thus, the first study reveals that RIM restores adipocyte morphology and prevents further fat-accumulation by down-regulating genes involved in lipid accumulation. RIM improves insulin sensitivity by inhibiting lipolysis, reducing adipose tissue inflammation and most importantly, elevating the plasma levels as well as the transcript levels of adiponectin.; In the second study, we wanted to study the molecular effects of RIM treatment on hepatic insulin sensitivity. We hypothesized that the effect of RIM on the liver may be mediated by adiponectin delivery from visceral fat to the liver. To study this, we measured the transcript levels of adiponectin receptor (AdipoR1 and AdipoR2) in the liver tissue as also, their downstream effectors namely, PPAR-α, carnitine palmitoyl transferase 1 (CPT-1α) and uncoupling protein 2 (UCP2), all of which are involved in lipid oxidation. We found RIM treatment to restore AdipoR1 expression to pre-fat control (basal) levels and increase AdipoR2 expression by 86% above basal levels. We also found RIM to increase PPAR-α, CPT-1α and UCP2 by 7 fold, 4.5 fold and 3.4 fold respectively as compared to fat-feeding, indicating increased rate of lipid oxidation by RIM treatment.; In summary we can conclude that increased delivery of adiponectin from visceral fat to the liver upon RIM treatment may have a beneficial effect on the liver by reducing fat accumulation in liver by increased fat oxidation thus, channeling the lipid droplets to the mitochondria. Hence, rimonabant may play a hepatoprotective role in obesity and may have an important pharmacological application in diabetes. |
| Keyword | rimonabant; adipose tissue; liver; inflammation; insulin resistance |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2706 |
| Rights | Iyer, Malini Subramanian |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Iyer-3349 |
| Archival file | uscthesesreloadpub_Volume40/etd-Iyer-3349.pdf |
Description
| Title | Page 1 |
| Full text | MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF CB1 ANTAGONISM IN CANINE MODEL OF OBESITY by Malini Subramanian Iyer A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2009 Copyright 2009 Malini Subramanian Iyer |
Comments
Post a Comment for Page 1
