The worldwide obesity epidemic1 makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates2,3. Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived 14C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.
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The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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We would like to acknowledge the assistance of research nurses, Y. Widlund and K. Hertel, as well as laboratory technician K. Wåhlén. This study was supported by grants from the Stockholm County Council (no. ALF SLL20160040 to M.R. and CIMED project code no. 3115 to P.A.), Swedish Research Council (no. K2014-54×−14510-12-5 to M.R., no. K2012-55×-01034-46-5 to P.A. and no. 542-2013-8358 to K.S.), the Strategic Research Program for Diabetes at Karolinska Institutet (no. H721309942 to M.R., no. H721105932 to P.A. and no. C5471152 to K.S.), the Novo Nordisk Foundation (no. 120C101637 to P.A., the Tripartite Immunometabolism Consortium no. NNF15CC0018486 and MSAM consortium no. NNF15SA0018346 to M.R. and an Excellence Project Award no. NNF12OC1016064 to K.S.), the Swedish Diabetes Foundation (no. DIA2016-097 to M.R.), Karolinska Institutet/Astra Zeneca Integrated Cardiometabolic Centre (no. H725701603 to K.S.) and the Vallee Foundation Vallee Scholar Award (no. C5471234 to K.S.). D.P.A. was supported by The Swedish Society of Medicine (no. H721748513) and the Stockholm County Council (no. K0138-2015). A.T. was supported by The Erling-Persson Family foundation (project code no. 140604). S.B. was supported by the Institut rhônalpin des systèmes complexes (project code no. 12554).
The authors declare no competing interests.
Peer review information: Jennifer Sargent and Joao Monteiro were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Values are the mean ± s.d. and (range). Conditions are compared using a paired t-test. Sex distribution between weight groups had a P value of 0.74 in cohort 1 by Fisher’s exact test. Cohort 2 was composed of women only. Body fat was measured with bioimpedance. See Methods for a definition of weight groups in cohort 1.
Cohort 1 was investigated twice with approximately a 13-year interval. The open circles are the first (baseline) and the closed circles the second (follow-up) examination. A large interindividual variation was observed. Despite this, lipid age increased in 42 out of 54 participants examined (P < 0.0001 by two-sample paired sign test).
Simulation of lipid dynamics (see and equation (13)) with estimated Kin and Kout for 33 individuals in cohort 2 for whom all data were available. Simulations (gray) closely follow the estimated lipid age (red) if estimates are consistent with the equilibrium assumption. For nine individuals, the simulation deviated significantly, indicating that the equilibrium assumption might not hold, leading to underestimating the true removal rate (and overestimating the true Kin).
Extended Data Fig. 4 Relationship between lipid age at first examination and changes in body composition over time (cohort 2).
Relationship between lipid age at first examination and changes (second minus first examination) in body composition over time (cohort 2). a, Percentage change in BMI. b, Changes (Δ) in total fat mass determined by DEXA. c, Changes (Δ) in abdominal subcutaneous fat mass corresponding to the site of adipose biopsy (ESAT). Cohort 2 was examined by linear regression. The number of individuals (n) are indicated. See Methods for further details.
a,b, Relationship between changes (Δ, second minus first examination) in lipid age and FLI (a) or EVAT (b) in cohort 2. Cohort 2 was examined using linear regression. The number of individuals (n) are indicated. See Methods for further details.
Relationship between changes (Δ, second minus first examination) in eating behavior and lipid age in cohort 2. a,b, The questionnaire on eating behavior (BITE) was used and is detailed in the Methods. BITE-A, magnitude of symptoms; BITE-B, severity of symptoms. Data were examined using linear regression; r and P values are shown. The number of individuals (n) are indicated.
Extended Data Fig. 7 Relationship between lipid age and measures of indirect calorimetry at first examination.
a, Data for resting energy expenditure. b, Data for respiratory quotient. Values for both cohorts combined were subjected to linear regression analysis. n = 51 and 41 for cohorts 1 and 2, respectively. r and P values are shown. When the cohorts were analyzed separately, the correlation parameters were r = 0.02–0.12 (a) and P = 0.45–0.89 (b). Data were examined by linear regression; r and P values are shown. The number of individuals (n) are indicated.
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Arner, P., Bernard, S., Appelsved, L. et al. Adipose lipid turnover and long-term changes in body weight. Nat Med 25, 1385–1389 (2019). https://doi.org/10.1038/s41591-019-0565-5
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