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Dynamics of human adipose lipid turnover in health and metabolic disease

Peter Arner, Samuel Bernard, Mehran Salehpour, Göran Possnert, Jakob Liebl, Peter Steier, Bruce A. Buchholz, Mats Eriksson, Erik Arner, Hans Hauner, Thomas Skurk, Mikael Rydén (+2 others)
2011 Nature  
Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes 1 . Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, here we determined lipid age by measuring 14 C derived from above ground nuclear bomb tests in adipocyte lipids. We report that during the average ten-year lifespan of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a
more » ... wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate (lipolysis followed by oxidation) is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidaemia, familial combined hyperlipidaemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis, and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal have different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidaemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease. A major function of adipose tissue is to store and release fatty acids, which are incorporated into adipocyte triglycerides according to whole-body energy demands. Body fat mass is determined by the balance between triglyceride storage and removal in adipocytes, by either enzymatic hydrolysis (lipolysis) and subsequent fatty acid oxidation and/or ectopic deposition in non-adipose tissues. Little is known about the dynamics of these processes in humans. Although isotope tracer methods have been used to estimate lipid turnover in human adipose tissue, these studies have been limited to short-term experimental conditions 1-4 . To study long-term adipose tissue lipid turnover in vivo and across the adult lifespan, we developed a method to retrospectively determine the age of adipocyte triglycerides in humans. Triglycerides are the major component of the adipocyte lipid droplet. Lipid age was assessed by measuring the 14 C content in the lipid compartment of adipocytes from human subcutaneous adipose tissue, the major fat depot in humans. 14 C levels in the atmosphere remained remarkably stable until above ground nuclear bomb tests between approximately 1955 and 1963 caused a significant increase in 14 C relative to stable carbon isotope levels 5 (Fig. 1a) . After the Limited Nuclear Test Ban Treaty was signed in 1963, 14 C levels in the atmosphere decreased exponentially. This is not due to radioactive decay (half-life (T 1/2 ) for 14 C is 5,730 years), but to diffusion of 14 CO 2 out of the atmosphere 6 . 14 C in the atmosphere oxidises to form CO 2 , which is taken up in the biotope by photosynthesis. Because we eat plants, or animals that live off plants, the 14 C content in the atmosphere is directly mirrored in the human body. Radiocarbon dating has been used to study the incorporation of atmospheric 14 C into DNA to determine the age of different human cell types, including adipocytes 7-11 . Here, we compared the incorporation of 14 C into adipocyte triglycerides with the dynamic changes in atmospheric 14 C described earlier. Triglyceride age was determined by using a linear lipid replacement model in which the age distribution of lipids within an individual was exponentially distributed corresponding to a constant turnover rate (per year) 12 . The associated mean age, termed lipid age, is the inverse of the turnover rate and reflects the irreversible removal of lipids from adipose stores ( Supplementary Information 1 and Fig. 1 of Supplementary Information 1) . Earlier studies indicate that triglycerides in adipose tissue form two distinct pools with high or low turnover rates, respectively 13,14 . Our data, obtained from individuals born before, during and after bomb testing, do not support the hypothesis of dual large lipid pools with different half-lives (Fig. 1b) . 14 C data were modelled according to one or more pools of lipids with different lipid removal rates (Supplementary Information 1). The existence of a very small pool of younger lipids cannot be excluded based on data modelling ( Supplementary Information 1 and Fig. 2 of Supplementary Information 1) . According to a two-pool model the influence on the turnover rate is proportional to the fraction of lipid in the small pool. Triglyceride exchange between adipocytes and other small storage pools can affect turnover estimates. The two-pools model shows, however, that the non-adipose pool can be neglected when it makes up less than 20% of the lipids (Supplementary Information 1, Fig. 3 ). Small pools with high turnover are more important for short-term (days or weeks) than long-term (years) triglyceride turnover. Mean lipid age was 1.6 years (Fig. 1c) , which is in the same range as in short-term turnover studies 4 . The distribution of lipid age was compared with that of adipocyte age reported previously in a comparable cohort 9 . The mean age of adipocytes was 9.5 years (Fig. 1d) . This implies that triglycerides, on average, are replaced six times during the lifespan of the adipocyte, enabling a dynamic regulation of lipid storage and mobilization over time. There is a large variation in adipocyte size within and between individuals (Supplementary Information 2, Supplementary Table 1) 15 . However, it is unlikely that the rate of triglyceride removal from adipocytes is important for these variations, as lipid age was not related to adipocyte size when set in relation to the body fat mass (Fig. 2a, b) , nor was there a difference in lipid age between large and small adipocytes of the same adipose tissue sample (Fig. 2c, d) . These data indicate that there is a continuous exchange of lipids between adipocytes within the adipose tissue that is not dependent on adipocyte size. Fatty acids produced by lipolysis in one adipocyte could, for example, be taken up
doi:10.1038/nature10426 pmid:21947005 pmcid:PMC3773935 fatcat:ub745qtjdjfkvg2ncekqk6xwhi

Dynamics of fat cell turnover in humans

Kirsty L. Spalding, Erik Arner, Pål O. Westermark, Samuel Bernard, Bruce A. Buchholz, Olaf Bergmann, Lennart Blomqvist, Johan Hoffstedt, Erik Näslund, Tom Britton, Hernan Concha, Moustapha Hassan (+3 others)
2008 Nature  
Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes 1,2 . Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history 3 . The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought
more » ... o be most important 4,5 . Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14 C derived from nuclear bomb tests in genomic DNA 6 . Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity. The fat mass can expand by increasing the average fat cell volume and/or the number of adipocytes. Increased fat storage in fully differentiated adipocytes, resulting in enlarged fat cells, is well documented and is thought to be the most important mechanism whereby fat depots increase in adults 4,5 . To analyse the contribution of the fat cell volume in adipocytes to the size of the fat mass, we first analysed the relationship between fat cell volume and total body fat mass (directly measured with bioimpedance or estimated from body mass index (BMI), sex and age in a large cohort of adults). As expected, there was a positive correlation between the measures of fat mass and fat cell volume both in subcutaneous fat (Fig. 1a-c) , which represents about 80% of all fat, and in visceral fat (Fig. 1d ), which has a strong link to metabolic complications of obesity. However, the relationship between fat cell volume and fat mass markedly differed from a linear relationship (likelihood ratio test P , 0.001, and Akaike information criterion, described in Supplementary Information 1) in both subcutaneous and visceral adipose regions and both sexes, indicating that fat mass is determined by both adipocyte number and size. In the nonlinear case, both fat cell number and fat cell size determine fat mass. If the relationship had been linear, fat cell volume would be the only important determinant of fat mass. The generation of adipocytes is a major factor behind the growth of adipose tissue during childhood 7 , but it is unknown whether the number of adipocytes changes during adulthood. We assessed the total adipocyte number in 687 adult individuals and combined this data with previously reported results for children and adolescents 8 . Although the total adipocyte number increased in childhood and adolescence, this number levelled off and remained constant in adulthood in both lean and obese individuals (adults over 20 yr, grouped in 5-yr bins; ANOVA, lean P 5 0.68, obese P 5 0.21; Fig. 2a and Supplementary Information 3) . Thus, the difference in adipocyte number between lean and obese individuals is established during childhood 7,8 and the total number of adipocytes for each weight category stays constant during adulthood (Fig. 2b ). The small variation in adipocyte number for each BMI category demonstrates that this is a stable cell population during adulthood. To analyse whether alterations in adipocyte number may contribute to changed fat mass under extreme conditions, we next asked whether fat cell number is reduced during major weight loss (mean body weight loss, 18 6 11%, mean 6 s.d.) by radical reduction in calorie intake by bariatric surgery (reduction of the stomach with the purpose of facilitating weight loss). The surgical treatment resulted in a significant decrease in BMI and fat cell volume; however, this failed to reduce adipocyte cell number two years post surgery (Fig. 2b, c and Supplementary Information 4) , in line with previous studies using different methodology 9-12 . Similar results were found in a complementary longitudinal study 13 . Ref. 13 found that significant weight gain (15-25%) over several months in non-obese adult men resulted in a significant increase in body fat, which was accompanied by an increase in adipocyte volume, but no change in adipocyte number. Similar to our findings, subsequent weight loss back to baseline resulted in a decrease of adipocyte volume, but, again, no change in adipocyte number. Although we cannot rule out that a more prolonged period of weight gain in adulthood could result in an increase in adipocyte number, these results and ours indicate that fat cell number is largely set by early adulthood and that changes in fat mass in adulthood can mainly be attributed to changes in fat cell volume. This may indicate that the number of adipocytes is set by early adulthood with no subsequent cell turnover. Alternatively, the generation of adipocytes may be balanced by adipocyte death, with the total number being tightly regulated and constant. We next set out to establish whether adipocytes are replaced during adulthood, and, if so, at what rate. Adipocytes can be generated from adult human mesenchymal stem cells and pre-adipocytes in vitro 14 and may undergo apoptosis or necrosis 15-17 , but it is unclear whether adipocytes are generated in vivo 14 . Cell turnover has been difficult to study in humans. Methods used in experimental animals, such as the incorporation of labelled nucleotides, cannot readily be adapted for use in humans owing to potential toxicity. The detection of cells expressing molecular markers of proliferation can give
doi:10.1038/nature06902 pmid:18454136 fatcat:mvkcs7bkwjc4lbvkzhztldmluy

Genetic Predisposition for Type 2 Diabetes, but Not for Overweight/Obesity, Is Associated with a Restricted Adipogenesis

Peter Arner, Erik Arner, Ann Hammarstedt, Ulf Smith, Massimo Federici
2011 PLoS ONE  
In order to differentiate between hypertrophic and hyperplastic obesity, Arner et al.  ... 
doi:10.1371/journal.pone.0018284 pmid:21532749 pmcid:PMC3075240 fatcat:jnqm7e3bzfbvdcahexb5awcnmq

Fatty Acids, Obesity and Insulin Resistance

Peter Arner, Mikael Rydén
2015 Obesity Facts  
Objective: Although elevated free fatty acid (FFA) levels in obesity have been considered to be of importance for insulin resistance, a recent meta-analysis suggested normal FFA levels in obese subjects. We investigated fasting circulating FFA and glycerol levels in a large cohort of non-obese and obese subjects. Methods: Subjects recruited for a study on obesity genetics were investigated in the morning after an overnight fast (n = 3,888). Serum FFA (n = 3,306), plasma glycerol (n = 3,776),
more » ... insulin sensitivity index (HOMA-IR,n = 3,469) were determined. Obesity was defined as BMI ≥ 30 kg/m 2 and insulin resistance as HOMA-IR ≥ 2.21. Results: In obese subjects, circulating FFA and glycerol levels were higher than in non-obese individuals (by 26% and 47%, respectively; both p < 0.0001). Similar results were obtained if only men, women or medication-free subjects were investigated. Insulin resistance and type 2 diabetes were associated with a further minor increase in FFA/glycerol among obese subjects. When comparing insulin-sensitive non-obese with insulin-sensitive or -resistant obese individuals, FFA and glycerol were 21-29% and 43-49% higher in obese individuals, respectively. Conclusion: Circulating FFA and glycerol levels are markedly elevated in obesity but only marginally influenced by insulin resistance and type 2 diabetes. Whether these differences persist during diurnal variations in circulating FFA/glycerol, remains to be established.
doi:10.1159/000381224 pmid:25895754 pmcid:PMC5644864 fatcat:htx43wyvs5dyfi74ndayk7fd6u

Catecholamine-induced lipolysis in obesity

Peter Arner
1999 International Journal of Obesity  
Lipolysis in obesity P Arner There is both direct and indirect evidence that catecholamine-induced lipolysis is under hereditary in¯uence.  ... 
doi:10.1038/sj.ijo.0800789 pmid:10193856 fatcat:r72ak3q3hjeblfll6l77hxfsl4

Datasets of genes coexpressed with FBN1 in mouse adipose tissue and during human adipogenesis

Margaret R. Davis, Erik Arner, Cairnan R.E. Duffy, Paul A. De Sousa, Ingrid Dahlman, Peter Arner, Kim M. Summers
2016 Data in Brief  
This article contains data related to the research article entitled "Expression of FBN1 during adipogenesis: relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions" [1] . The article concerns the expression of FBN1, the gene encoding the extracellular matrix protein fibrillin-1, during adipogenesis in vitro and in relation to adipose tissue in vivo. The encoded protein has recently been shown to produce a short glucogenic peptide hormone, (Romere et al., 2016) [2],
more » ... d this gene is therefore a key gene for regulating blood glucose levels. FBN1 and coexpressed genes were examined in mouse strains and in human
doi:10.1016/j.dib.2016.06.055 pmid:27508231 pmcid:PMC4959917 fatcat:4wkx6g7nkffihjgwmpexv5qg6e

MicroRNA-27a/b-3p and PPARG regulate SCAMP3 through a feed-forward loop during adipogenesis

Agné Kulyté, Kelvin Ho Man Kwok, Michiel de Hoon, Piero Carninci, Yoshihide Hayashizaki, Peter Arner, Erik Arner
2019 Scientific Reports  
MicroRNAs (miRNA) modulate gene expression through feed-back and forward loops. Previous studies identified miRNAs that regulate transcription factors, including Peroxisome Proliferator Activated Receptor Gamma (PPARG), in adipocytes, but whether they influence adipogenesis via such regulatory loops remain elusive. Here we predicted and validated a novel feed-forward loop regulating adipogenesis and involved miR-27a/b-3p, PPARG and Secretory Carrier Membrane Protein 3 (SCAMP3). In this loop,
more » ... ression of both PPARG and SCAMP3 was independently suppressed by miR-27a/b-3p overexpression. Knockdown of PPARG downregulated SCAMP3 expression at the late phase of adipogenesis, whereas reduction of SCAMP3 mRNA levels increased PPARG expression at early phase in differentiation. The latter was accompanied with upregulation of adipocyte-enriched genes, including ADIPOQ and FABP4, suggesting an anti-adipogenic role for SCAMP3. PPARG and SCAMP3 exhibited opposite behaviors regarding correlations with clinical phenotypes, including body mass index, body fat mass, adipocyte size, lipolytic and lipogenic capacity, and secretion of pro-inflammatory cytokines. While adipose PPARG expression was associated with more favorable metabolic phenotypes, SCAMP3 expression was linked to increased fat mass and insulin resistance. Together, we identified a feed-forward loop through which miR-27a/b-3p, PPARG and SCAMP3 cooperatively fine tune the regulation of adipogenesis, which potentially may impact whole body metabolism.
doi:10.1038/s41598-019-50210-3 pmid:31554889 pmcid:PMC6761119 fatcat:odasfn3bnrfidomt2yaloukad4

Obesity — a genetic disease of adipose tissue?

Peter Arner
2000 British Journal of Nutrition  
As discussed (Hill & Peters, 1998) the environmental contribution to the obesity epidemic is apparent.  ...  Arner obesity, whereas peripheral obesity is the most common form among women.  ... 
doi:10.1017/s0007114500000891 fatcat:kfdp3jzglva3vlaakutqwvsxeu

Dynamics of Fat Cell Turnover in Humans

Kirsty L. Spalding, Erik Arner, Pål O. Westermark, Samuel Bernard, Bruce A. Buchholz, Olaf Bergmann, Lennart Blomqvist, Johan Hoffstedt, Erik Näslund, Tom Britton, Hernan Concha, Moustapha Hassan (+3 others)
2008 Obstetrical and Gynecological Survey  
With two catalytic activities and many substrates, how does HIV's reverse transcriptase enzyme know what to do to which substrate? Zooming in on the enzyme's molecular interactions provides tantalizing clues.
doi:10.1097/01.ogx.0000325910.81966.ac fatcat:lg7b5gbtlrfsbpibhwf5mlllia

Microdialysis: use in human exercise studies

Peter Arner
1999 Proceedings of the Nutrition Society  
It was not until recently that microdialysis was used to study the function of peripheral tissues (Arner & Bolinder, 1991; Arner & Bülow, 1993; Lafontan & Arner, 1996) .  ...  & Bülow, 1993; Lafontan & Arner, 1996) .  ... 
doi:10.1017/s0029665199001214 pmid:10817158 fatcat:s6wil4rbmjaw3htqahkdpxdlzi

Turnover of human fat cells and their lipid content

Peter Arner
2015 Acta Veterinaria Scandinavica  
• Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit this article as: Arner: Turnover of human fat cells and their lipid content.  ...  Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar © 2015 Arner  ... 
doi:10.1186/1751-0147-57-s1-k1 fatcat:c2owqepq2nc3xf7qxdpezdiohe

Changes in Subcutaneous Fat Cell Volume and Insulin Sensitivity After Weight Loss

Daniel P. Andersson, Daniel Eriksson Hogling, Anders Thorell, Eva Toft, Veronica Qvisth, Erik Näslund, Anders Thörne, Mikael Wirén, Patrik Löfgren, Johan Hoffstedt, Ingrid Dahlman, Niklas Mejhert (+3 others)
2014 Diabetes Care  
OBJECTIVE Large subcutaneous fat cells associate with insulin resistance and high risk of developing type 2 diabetes. We investigated if changes in fat cell volume and fat mass correlate with improvements in the metabolic risk profile after bariatric surgery in obese patients. RESEARCH DESIGN AND METHODS Fat cell volume and number were measured in abdominal subcutaneous adipose tissue in 62 obese women before and 2 years after Roux-en-Y gastric bypass (RYGB). Regional body fat mass by
more » ... y X-ray absorptiometry; insulin sensitivity by hyperinsulinemic-euglycemic clamp; and plasma glucose, insulin, and lipid profile were assessed. RESULTS RYGB decreased body weight by 33%, which was accompanied by decreased adipocyte volume but not number. Fat mass in the measured regions decreased and all metabolic parameters were improved after RYGB (P < 0.0001). Whereas reduced subcutaneous fat cell size correlated strongly with improved insulin sensitivity (P = 0.0057), regional changes in fat mass did not, except for a weak correlation between changes in visceral fat mass and insulin sensitivity and triglycerides. The curve-linear relationship between fat cell size and fat mass was altered after weight loss (P = 0.03). CONCLUSIONS After bariatric surgery in obese women, a reduction in subcutaneous fat cell volume associates more strongly with improvement of insulin sensitivity than fat mass reduction per se. An altered relationship between adipocyte size and fat mass may be important for improving insulin sensitivity after weight loss. Fat cell size reduction could constitute a target to improve insulin sensitivity. Obesity is associated with insulin resistance and dyslipidemia and also with a very high risk of developing type 2 diabetes. Interestingly, studies of bariatric surgery (i.e., techniques that reduce or bypass the stomach in order to achieve weight reduction) show, first, that there is no clear quantitative relationship between the weight loss induced by various surgical procedures and the degree of normalization in insulin sensitivity and other metabolic parameters and, second, that metabolism is markedly improved before any significant weight loss is achieved (1,2) . In a hallmark study by Klein et al. (3) , a large amount of subcutaneous abdominal adipose tissue was removed from obese subjects by liposuction. This was not accompanied by
doi:10.2337/dc13-2395 pmid:24760260 fatcat:fh3bfwnzvbheflw4gip2ozkhfq

Expression of FBN1 during adipogenesis: Relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions

Margaret R. Davis, Erik Arner, Cairnan R.E. Duffy, Paul A. De Sousa, Ingrid Dahlman, Peter Arner, Kim M. Summers
2016 Molecular Genetics and Metabolism  
Arner, C.R.E. Duffy, P.A. De Sousa, I. Dahlman, P. Arner, K.M. Summers, Transcriptomic analysis of adipogenesis: coexpression of genes with FBN1 in human and mouse Data in Brief Submitted (2016).  ...  Arner, J. Laurencikiene, LXR is a negative regulator of glucose uptake in human adipocytes Diabetologia 56 (2013) 2044-2054. [42] A.M. Rodriguez, D. Pisani, C.A. Dechesne, C. Turc-Carel, J.Y.  ... 
doi:10.1016/j.ymgme.2016.06.009 pmid:27386756 pmcid:PMC5044862 fatcat:zkyuuccndngchigmtanql47b4e

NPC1 in human white adipose tissue and obesity

Clara Bambace, Ingrid Dahlman, Peter Arner, Agné Kulyté
2013 BMC Endocrine Disorders  
Genetic studies have implicated the NPC1 gene (Niemann Pick type C1) in susceptibility to obesity. Methods: To assess the potential function of NPC1 in obesity, we determined its expression in abdominal white adipose tissue (WAT) in relation to obesity. NPC1 mRNA was measured by RT-qPCR in lean and obese individuals, paired samples of subcutaneous (sc) and omental (om) WAT, before and after weight loss, in isolated adipocytes and intact adipose pieces, and in primary adipocyte cultures during
more » ... ipocyte differentiation. NPC1 protein was examined in isolated adipocytes. Results: NPC1 mRNA was significantly increased in obese individuals in scWAT and omWAT and downregulated by weight loss. NPC1 mRNA was enriched in isolated fat cells of WAT, in scWAT versus omWAT but not modified during adipocyte differentiation. NPC1 protein mirrored expression of mRNA in lean and obese individuals. Conclusions: NPC1 is highly expressed in human WAT adipocytes with increased levels in obese. These results suggest that NPC1 may play a role in adipocyte processes underlying obesity.
doi:10.1186/1472-6823-13-5 pmid:23360456 pmcid:PMC3566954 fatcat:jd5ezwatq5cs7d5vli7sqcwm4a

Transplanted Bone Marrow-Derived Cells Contribute to Human Adipogenesis

Mikael Rydén, Mehmet Uzunel, Joanna L. Hård, Erik Borgström, Jeff E. Mold, Erik Arner, Niklas Mejhert, Daniel P. Andersson, Yvonne Widlund, Moustapha Hassan, Christina V. Jones, Kirsty L. Spalding (+6 others)
2015 Cell Metabolism  
The cell volume was calculated from the diameter using a described formula (Arner et al., 2013) .  ... 
doi:10.1016/j.cmet.2015.06.011 pmid:26190649 fatcat:2mq5ecm6b5hqzd75ecnmry623m
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