Adipose tissue metabolism in acquired obesity

Sini Heinonen

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Obesity is a major health problem and is increasing rapidly both in developed and developing countries worldwide. Treatment of obesity is difficult, expensive and often fails. Obesity increases the likelihood for many diseases, such as type 2 diabetes, coronary heart disease, metabolic syndrome, hyperlipidemia and some types of cancer. We still lack a meaningful understanding of the factors behind this complex disease and therefore any proper means to battle it. Only lately, adipose tissue and especially its mitochondria have been recognized as important contributors to whole-body energy balance and the development of obesity. This thesis investigates the biological pathways in adipose tissue that lead to the development of metabolic complications in early-onset obesity in young healthy twins. The aim was to study how acquired obesity affects adipose tissue and adipocyte function and how these link to whole body metabolism. The rare weight-discordant monozygotic (MZ) co-twin setting used in this study, is uniquely positioned to disentangle acquired and inherited metabolic pathways to disease in obesity. MZ twin pairs discordant for obesity enable controlling for genetic background, age, sex and early environmental influences. As MZ twins are fully identical at the level of genome sequence, the observed differences between the co-twins can be assumed to be acquired. This is a major strength of our study regarding a polygenic and multifactorial trait as obesity. Adipocyte hypertrophy in adipose tissue is one of the main features of obesity. The first study of the thesis investigated adipose tissue hypertrophy and hyperplasia in acquired obesity and its associations to whole body metabolism and gene expression pathways of the adipose tissue. We showed a high within-pair resemblance in adipocyte size and number suggesting that the adipocyte phenotype is genetic or due to shared environmental factors. Hypertrophy (large size) and low number of adipocytes in acquired obesity was related to metabolic dysfunction in obesity and associated with the disturbances in mitochondrial function and with increased cell death within the adipose tissue. In the second study we investigated how transcriptional pathways of subcutaneous adipose tissue and the liver fat associate with metabolically healthy obesity a phenomenon where some of the obese individuals stay free from metabolic complications usually associated with weight gain. We showed for the first time in twins that the amount of liver fat is a key clinical determinant of metabolic health and that low liver fat associates with maintenance of high mitochondrial transcription and lack of inflammation in subcutaneous adipose tissue. In further investigations we addressed mitochondrial biogenesis and oxidative metabolism in detail. The third and fourth studies concentrated on mitochondrial biogenesis in adipose tissue and in adipocytes, respectively. The novel findings in the third study were that obesity is related to reduced mitochondrial mass and oxidative metabolic activity in subcutaneous adipose tissue, both in the nuclear and in the mitochondrial transcription level, as well as decreased protein levels in the OXPHOS system, especially OXPHOS complex subunits I and IV. The mitochondrial dysfunction paralleled whole body insulin resistance and low-grade systemic inflammation. Remarkably, these changes were seen already at the early stages of acquired obesity. In the fourth study, we showed that the global downregulation of mitochondrial transcriptional signature in acquired obesity originates at least partly from the adipocyte cells of adipose tissue. This research resulted in better understanding of the factors behind metabolic complications in acquired obesity. Development of obesity seems to associate with mitochondrial dysfunction in adipose tissue. The decreased function of mitochondria was evident at the level of both nuclear gene expression level and mitochondrial gene expression, as well as mitochondrial protein levels. These changes associated with metabolic disturbances of obesity. With rare obesity-discordant MZ twins we have been able to show that the changes are not genetic but result from acquired factors. However, as there was a remarkable similarity of adipocyte size and especially number between the co-twins, responses to obesity may have a partial genetic basis. With low capacity to adipocyte hypertrophy, excess fat may accumulate to liver and other tissues. Liver fat content is a clear determinant of metabolic health in acquired obesity. The results of my thesis as a whole suggest that obesity-associated metabolic disturbances might be halted by improving mitochondrial number and/or activity in adipose tissue.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-2364-0
Electronic ISBNs978-951-51-2365-7
Publication statusPublished - 2016
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3121 Internal medicine

Cite this

Heinonen, S. (2016). Adipose tissue metabolism in acquired obesity. Helsinki: University of Helsinki.
Heinonen, Sini. / Adipose tissue metabolism in acquired obesity. Helsinki : University of Helsinki, 2016. 143 p.
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title = "Adipose tissue metabolism in acquired obesity",
abstract = "Obesity is a major health problem and is increasing rapidly both in developed and developing countries worldwide. Treatment of obesity is difficult, expensive and often fails. Obesity increases the likelihood for many diseases, such as type 2 diabetes, coronary heart disease, metabolic syndrome, hyperlipidemia and some types of cancer. We still lack a meaningful understanding of the factors behind this complex disease and therefore any proper means to battle it. Only lately, adipose tissue and especially its mitochondria have been recognized as important contributors to whole-body energy balance and the development of obesity. This thesis investigates the biological pathways in adipose tissue that lead to the development of metabolic complications in early-onset obesity in young healthy twins. The aim was to study how acquired obesity affects adipose tissue and adipocyte function and how these link to whole body metabolism. The rare weight-discordant monozygotic (MZ) co-twin setting used in this study, is uniquely positioned to disentangle acquired and inherited metabolic pathways to disease in obesity. MZ twin pairs discordant for obesity enable controlling for genetic background, age, sex and early environmental influences. As MZ twins are fully identical at the level of genome sequence, the observed differences between the co-twins can be assumed to be acquired. This is a major strength of our study regarding a polygenic and multifactorial trait as obesity. Adipocyte hypertrophy in adipose tissue is one of the main features of obesity. The first study of the thesis investigated adipose tissue hypertrophy and hyperplasia in acquired obesity and its associations to whole body metabolism and gene expression pathways of the adipose tissue. We showed a high within-pair resemblance in adipocyte size and number suggesting that the adipocyte phenotype is genetic or due to shared environmental factors. Hypertrophy (large size) and low number of adipocytes in acquired obesity was related to metabolic dysfunction in obesity and associated with the disturbances in mitochondrial function and with increased cell death within the adipose tissue. In the second study we investigated how transcriptional pathways of subcutaneous adipose tissue and the liver fat associate with metabolically healthy obesity a phenomenon where some of the obese individuals stay free from metabolic complications usually associated with weight gain. We showed for the first time in twins that the amount of liver fat is a key clinical determinant of metabolic health and that low liver fat associates with maintenance of high mitochondrial transcription and lack of inflammation in subcutaneous adipose tissue. In further investigations we addressed mitochondrial biogenesis and oxidative metabolism in detail. The third and fourth studies concentrated on mitochondrial biogenesis in adipose tissue and in adipocytes, respectively. The novel findings in the third study were that obesity is related to reduced mitochondrial mass and oxidative metabolic activity in subcutaneous adipose tissue, both in the nuclear and in the mitochondrial transcription level, as well as decreased protein levels in the OXPHOS system, especially OXPHOS complex subunits I and IV. The mitochondrial dysfunction paralleled whole body insulin resistance and low-grade systemic inflammation. Remarkably, these changes were seen already at the early stages of acquired obesity. In the fourth study, we showed that the global downregulation of mitochondrial transcriptional signature in acquired obesity originates at least partly from the adipocyte cells of adipose tissue. This research resulted in better understanding of the factors behind metabolic complications in acquired obesity. Development of obesity seems to associate with mitochondrial dysfunction in adipose tissue. The decreased function of mitochondria was evident at the level of both nuclear gene expression level and mitochondrial gene expression, as well as mitochondrial protein levels. These changes associated with metabolic disturbances of obesity. With rare obesity-discordant MZ twins we have been able to show that the changes are not genetic but result from acquired factors. However, as there was a remarkable similarity of adipocyte size and especially number between the co-twins, responses to obesity may have a partial genetic basis. With low capacity to adipocyte hypertrophy, excess fat may accumulate to liver and other tissues. Liver fat content is a clear determinant of metabolic health in acquired obesity. The results of my thesis as a whole suggest that obesity-associated metabolic disturbances might be halted by improving mitochondrial number and/or activity in adipose tissue.",
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Heinonen, S 2016, 'Adipose tissue metabolism in acquired obesity', Helsinki.

Adipose tissue metabolism in acquired obesity. / Heinonen, Sini.

Helsinki : University of Helsinki, 2016. 143 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Adipose tissue metabolism in acquired obesity

AU - Heinonen, Sini

N1 - M1 - 143 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2016

Y1 - 2016

N2 - Obesity is a major health problem and is increasing rapidly both in developed and developing countries worldwide. Treatment of obesity is difficult, expensive and often fails. Obesity increases the likelihood for many diseases, such as type 2 diabetes, coronary heart disease, metabolic syndrome, hyperlipidemia and some types of cancer. We still lack a meaningful understanding of the factors behind this complex disease and therefore any proper means to battle it. Only lately, adipose tissue and especially its mitochondria have been recognized as important contributors to whole-body energy balance and the development of obesity. This thesis investigates the biological pathways in adipose tissue that lead to the development of metabolic complications in early-onset obesity in young healthy twins. The aim was to study how acquired obesity affects adipose tissue and adipocyte function and how these link to whole body metabolism. The rare weight-discordant monozygotic (MZ) co-twin setting used in this study, is uniquely positioned to disentangle acquired and inherited metabolic pathways to disease in obesity. MZ twin pairs discordant for obesity enable controlling for genetic background, age, sex and early environmental influences. As MZ twins are fully identical at the level of genome sequence, the observed differences between the co-twins can be assumed to be acquired. This is a major strength of our study regarding a polygenic and multifactorial trait as obesity. Adipocyte hypertrophy in adipose tissue is one of the main features of obesity. The first study of the thesis investigated adipose tissue hypertrophy and hyperplasia in acquired obesity and its associations to whole body metabolism and gene expression pathways of the adipose tissue. We showed a high within-pair resemblance in adipocyte size and number suggesting that the adipocyte phenotype is genetic or due to shared environmental factors. Hypertrophy (large size) and low number of adipocytes in acquired obesity was related to metabolic dysfunction in obesity and associated with the disturbances in mitochondrial function and with increased cell death within the adipose tissue. In the second study we investigated how transcriptional pathways of subcutaneous adipose tissue and the liver fat associate with metabolically healthy obesity a phenomenon where some of the obese individuals stay free from metabolic complications usually associated with weight gain. We showed for the first time in twins that the amount of liver fat is a key clinical determinant of metabolic health and that low liver fat associates with maintenance of high mitochondrial transcription and lack of inflammation in subcutaneous adipose tissue. In further investigations we addressed mitochondrial biogenesis and oxidative metabolism in detail. The third and fourth studies concentrated on mitochondrial biogenesis in adipose tissue and in adipocytes, respectively. The novel findings in the third study were that obesity is related to reduced mitochondrial mass and oxidative metabolic activity in subcutaneous adipose tissue, both in the nuclear and in the mitochondrial transcription level, as well as decreased protein levels in the OXPHOS system, especially OXPHOS complex subunits I and IV. The mitochondrial dysfunction paralleled whole body insulin resistance and low-grade systemic inflammation. Remarkably, these changes were seen already at the early stages of acquired obesity. In the fourth study, we showed that the global downregulation of mitochondrial transcriptional signature in acquired obesity originates at least partly from the adipocyte cells of adipose tissue. This research resulted in better understanding of the factors behind metabolic complications in acquired obesity. Development of obesity seems to associate with mitochondrial dysfunction in adipose tissue. The decreased function of mitochondria was evident at the level of both nuclear gene expression level and mitochondrial gene expression, as well as mitochondrial protein levels. These changes associated with metabolic disturbances of obesity. With rare obesity-discordant MZ twins we have been able to show that the changes are not genetic but result from acquired factors. However, as there was a remarkable similarity of adipocyte size and especially number between the co-twins, responses to obesity may have a partial genetic basis. With low capacity to adipocyte hypertrophy, excess fat may accumulate to liver and other tissues. Liver fat content is a clear determinant of metabolic health in acquired obesity. The results of my thesis as a whole suggest that obesity-associated metabolic disturbances might be halted by improving mitochondrial number and/or activity in adipose tissue.

AB - Obesity is a major health problem and is increasing rapidly both in developed and developing countries worldwide. Treatment of obesity is difficult, expensive and often fails. Obesity increases the likelihood for many diseases, such as type 2 diabetes, coronary heart disease, metabolic syndrome, hyperlipidemia and some types of cancer. We still lack a meaningful understanding of the factors behind this complex disease and therefore any proper means to battle it. Only lately, adipose tissue and especially its mitochondria have been recognized as important contributors to whole-body energy balance and the development of obesity. This thesis investigates the biological pathways in adipose tissue that lead to the development of metabolic complications in early-onset obesity in young healthy twins. The aim was to study how acquired obesity affects adipose tissue and adipocyte function and how these link to whole body metabolism. The rare weight-discordant monozygotic (MZ) co-twin setting used in this study, is uniquely positioned to disentangle acquired and inherited metabolic pathways to disease in obesity. MZ twin pairs discordant for obesity enable controlling for genetic background, age, sex and early environmental influences. As MZ twins are fully identical at the level of genome sequence, the observed differences between the co-twins can be assumed to be acquired. This is a major strength of our study regarding a polygenic and multifactorial trait as obesity. Adipocyte hypertrophy in adipose tissue is one of the main features of obesity. The first study of the thesis investigated adipose tissue hypertrophy and hyperplasia in acquired obesity and its associations to whole body metabolism and gene expression pathways of the adipose tissue. We showed a high within-pair resemblance in adipocyte size and number suggesting that the adipocyte phenotype is genetic or due to shared environmental factors. Hypertrophy (large size) and low number of adipocytes in acquired obesity was related to metabolic dysfunction in obesity and associated with the disturbances in mitochondrial function and with increased cell death within the adipose tissue. In the second study we investigated how transcriptional pathways of subcutaneous adipose tissue and the liver fat associate with metabolically healthy obesity a phenomenon where some of the obese individuals stay free from metabolic complications usually associated with weight gain. We showed for the first time in twins that the amount of liver fat is a key clinical determinant of metabolic health and that low liver fat associates with maintenance of high mitochondrial transcription and lack of inflammation in subcutaneous adipose tissue. In further investigations we addressed mitochondrial biogenesis and oxidative metabolism in detail. The third and fourth studies concentrated on mitochondrial biogenesis in adipose tissue and in adipocytes, respectively. The novel findings in the third study were that obesity is related to reduced mitochondrial mass and oxidative metabolic activity in subcutaneous adipose tissue, both in the nuclear and in the mitochondrial transcription level, as well as decreased protein levels in the OXPHOS system, especially OXPHOS complex subunits I and IV. The mitochondrial dysfunction paralleled whole body insulin resistance and low-grade systemic inflammation. Remarkably, these changes were seen already at the early stages of acquired obesity. In the fourth study, we showed that the global downregulation of mitochondrial transcriptional signature in acquired obesity originates at least partly from the adipocyte cells of adipose tissue. This research resulted in better understanding of the factors behind metabolic complications in acquired obesity. Development of obesity seems to associate with mitochondrial dysfunction in adipose tissue. The decreased function of mitochondria was evident at the level of both nuclear gene expression level and mitochondrial gene expression, as well as mitochondrial protein levels. These changes associated with metabolic disturbances of obesity. With rare obesity-discordant MZ twins we have been able to show that the changes are not genetic but result from acquired factors. However, as there was a remarkable similarity of adipocyte size and especially number between the co-twins, responses to obesity may have a partial genetic basis. With low capacity to adipocyte hypertrophy, excess fat may accumulate to liver and other tissues. Liver fat content is a clear determinant of metabolic health in acquired obesity. The results of my thesis as a whole suggest that obesity-associated metabolic disturbances might be halted by improving mitochondrial number and/or activity in adipose tissue.

KW - Adipose Tissue

KW - +metabolism

KW - Adipocytes

KW - Body Mass Index

KW - Body Weight

KW - +physiology

KW - DNA, Mitochondrial

KW - Energy Metabolism

KW - Fatty Acids

KW - Fatty Liver

KW - Gene-Environment Interaction

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Inflammation

KW - Insulin Resistance

KW - Metabolome

KW - Mitochondria

KW - Mitochondrial Turnover

KW - +genetics

KW - Obesity

KW - +complications

KW - Subcutaneous Fat

KW - Twins, Monozygotic

KW - 3121 Internal medicine

M3 - Doctoral Thesis

SN - 978-951-51-2364-0

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

CY - Helsinki

ER -

Heinonen S. Adipose tissue metabolism in acquired obesity. Helsinki: University of Helsinki, 2016. 143 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 74/2016).