Carnitine, Choline and Caffeine Promote Fat Loss and Metabolism in Rats and Humans

290 Pages·2017·9.92 MB·English

by  Nobuko Hongu

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Doctoral Dissertations Graduate School
5-2002
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Nobuko Hongu
University of Tennessee, Knoxville
Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss
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Hongu, Nobuko, "Carnitine, Choline and Caffeine Promote Fat Loss and Metabolism in Rats and Humans.
" PhD diss., University of Tennessee, 2002.
https://trace.tennessee.edu/utk_graddiss/3818
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To the Graduate Council:
I am submitting herewith a dissertation written by Nobuko Hongu entitled "Carnitine, Choline
and Caffeine Promote Fat Loss and Metabolism in Rats and Humans." I have examined the final
electronic copy of this dissertation for form and content and recommend that it be accepted in
partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in
Human Ecology.
DiLeep S. Sachan, Major Professor
We have read this dissertation and recommend its acceptance:
Edward T. Howley, Naima Moustaid Moussa, Jean D. Skinner
Accepted for the Council:
Carolyn R. Hodges
Vice Provost and Dean of the Graduate School
(Original signatures are on file with official student records.)
To the Graduate Council:
I am submitting herewith a dissertation written by Nobuko Hongu entitled "Carnitine,
Choline and Caffeine Promote Fat Loss and Metabolism in Rats and Humans." I have
examined the final paper copy of this dissertation for form and content and recommend
that it be accepted in partial fulfilment of the requirements for the degree of Doctor of
Philosophy, with a major in Human Ecology.
an, D.V.M., Ph.D., Major Professor
we have read this dissertation
and recommend its acceptance:
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Edward T. Howley, Ph.D.
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DEDICATION
This dissertation is dedicated to my parents
Mr. Teruhiko Kikugawa and Mrs. Yoshiko Kikugawa,
for ensuring the quality of my early education;
and my husband
Dr. Yuji Hongu,
for his encouragement, patience, and support throughout this study.
11
ACKNOWLEDGMENTS
I would like to express my sincere appreciation to all those who contributed to the
success of this study. First and foremost, I must mention my committee members. Dr.
Dileep S. Sachan, my major professor, guided me throughout my graduate career and
provided numerous opportunities for practical training and financial support. He
introduced me to the importance of nutrient-nutrient interaction. Through his class, he
has taught me the value of nutrition under normal and disease conditions. It was a
privilege to work under the direction of such a talented scientist.
Dr. Nai'.ma Moustai'.d Moussa showed great interest in our research and spend
many hours discussing the importance of fat metabolism, always asking questions that
forced me to go back and reevaluate our perspective. Dr. Jean D. Skinner provided
valuable insights regarding the meaning of nutrient anlayses. Dr. Edward T. Howley, for
his knowledge of exercise gave me direction in my research. Their professionalism and
commitment to a high quality of research have been an inspiration for me to keep
searching for truth in my study.
I owe many thanks to the faculty of the Nutrition Department: Dr. James W.
Bailey, Dr. Betty Ruth Carruth, Dr. Betsy Haughton, Dr. Jay Whelan and Dr. Michael B.
Zemel. They managed to keep graduate school exciting and challenging through many
years. Additionally, I owe many thanks to the members of the Sachan's laboratory, Dr.
James W. Daily III, Dr. Mei-Shin Mong, and Dr. Ayub M. Yatim who taught me how to
run camitine assays and their own skills and techniques in the lab. I am extremely
grateful for the time we spent together and their friendship.
Ill
I also grateful to the former professors and the special friends, Dr. Ralph 0.
am
Blackwood, Dr. Nancy Paisley, Dr. Tuyoshi Shimizu, Mrs. Julia A. Eckard, Ms. Karen
Sprang and Ms. Denise Serrano, whose long-standing beliefs in my ability to complete
the study and produce a dissertation. They made this study possible by their friendship
and emotional support.
I can not forget to thank all men and women who came to participate our study.
Their efforts to follow the experimental procedures, which were tedious and time
consuming, were greatly appreciated. Without their help the project could not have
accomplished.
Finally, I am grateful to my parents Teruhiko Kikugawa and Yoshiko Kikugawa,
and my sister Ya suyo Hayashi, for their unwavering support through the years. My
husband, Yuji Hongu, who is a great chemist taught me basic organic chemistry day and
night without any hesitation, which greatly helped build my foundation of chemistry. He
took many responsibilities so that I could focus my time and effort on the completion of
this dissertation. His encouragement kept me going even when things appeared bleak and
slow.
This dissertation would not have been possible without assistance of those many
individuals. With all of my heart I thank them.
lV
ABSTRACT
Interaction of two nutrients, carnitine and choline, has been reported. Choline
supplementation causes a significant conservation of carnitine in normal healthy humans
and guinea pigs. The choline supplementation promoted tissue carnitine accretion,
particularly in skeletal muscle of guinea pigs, and livers of rats. Also, choline
supplemented guinea pigs had lower percentage of carcass fat and higher percentage of
protein but the body weights or the respiratory quotient (RQ) were not affected.
Based on these observations, we hypothesized that a combination of choline and
camitine may further increase camitine accretion by tissues, and if energy needs were
increased by exercise and fat mobilization was stimulated by caffeine, there may be
reduction in body fat. In other words, simultaneous availability of carnitine, choline, and
caffeine may induce mobilization, transport and delivery of fat as the energy substrate of
choice, and therefore, enhance utilization of fat. In a 2 x 2 factorial design, male
Sprague-Dawley rats were assigned to nonsupplemented and supplemented groups and
one-half of each group was exercised. Body weight was significantly reduced by exercise
only, however, regional fat pad weights and serum leptin concentration were significantly
reduced by the combination of carnitine, choline and caffeine supplements as well as by
exercise. Regardless of exercise, supplements significantly lowered triglycerides in
serum but increased triglycerides in the skeletal muscle.
We postulated that fat loss in rats was due to enhanced fat mobilization and fatty
acid oxidation. To support this, we determined the RQ and several metabolic markers of
fat oxidation in the rat model. No significant differences were found in the mean RQ
V
values of the groups at rest in all groups and at exhaustion between the two exercised
groups. However, increased maximal oxygen uptake (V0 max) and delayed exhaustion
2
time was found in the supplemented rats. Post-exercise concentrations of serum
triglycerides were decreased, but P-hydroxybutyrate, acylcarnitine and acetylcarnitine
were increased in the supplemented rats. The changes in serum metabolites were
complemented by the changes in the muscle and urinary metabolites. The magnitude of
increase in urinary acylcarnitine (34 to 45-fold) of the supplemented rats is a unique
effect of this combination of the supplements. Evidence indicates enhanced P-oxidation
of fatty acids without a change in the RQ because acetyl units were excreted in urine as
acetylcarnitine and not oxidized to carbon dioxide. For this phenomenon we proposed
the term, "fatty acid dumping".
Finally, we determined fat loss and metabolic effects of this unique nutrient­
nutrient interaction in humans. We asked, if the shift in tissue carnitine partitioning will
result in enhanced fat oxidation in humans. Healthy adults aged 18-54 y were randomly
assigned to a placebo or supplement groups. Supplementary choline and camitine
increased serum concentration of P-hydroxybutyrate. Another biochemical marker of
fatty acid oxidation, acetylcarnitine, was elevated about 2-fold and 3-fold in serum and
urine, respectively. Short-chain acylcarnitines were moderately elevated in serum but
significantly increased in the urine by the supplementation. The observations in humans
are consistent with those in rats. This research in rats and humans firmly established that
the supplementation with camitine, choline and caffeine promoted fatty acid oxidation to
short-chain fatty acids and their disposal in urine as acylcarnitines.
VI
TABLE OF CONTENTS
CHAPTER PAGE
I. INTRODUCTION 1
II. LITERATURE REVIEW 4
CARNITINE 4
Dietary Sources of Camit ine 6
Camitine Homeostasis 8
Supplement Forms of Camitine 13
Camitine Biosynthesis 14
Absorption 17
Transport and Tissue Uptake 18
Excretion
20
Functions 21
A. Mitochondrial fatty acid oxidation 21
B. Modulation of acyl-CoA/CoA ratio 23
Nutrient-Nutrient Interactions 25
Camitine Supplementation 31
A. Physical performance 31
B. Weight loss and management 38
CHOLINE 38
Dietary Sources of Choline 43
Choline Homeostasis 46
Choline Biosynthesis 47
Absorption 49
Transport and Tissue Uptake 50
Metabolism 51
Functions 54
Choline Supplementation 57
A. Nervous system and maintenance 57
of normal lipid profile
B. Physical performance 59
CAFFEINE 61
Dietary Sources and Consumption of Caffeine 66
Absorption 71
Transport and Tissue Uptake 71
Excretion 72
Metabolism 72
Vil