Dynamics of human adipose lipid turnover in health and metabolic disease

Abstract

Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes. 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 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.

Fig. 1

Atmospheric ¹⁴C over time. A: Above ground nuclear bomb testing during the period of the cold war caused an increase in atmospheric levels of ¹⁴C. These values decreased exponentially following implementation of a limited world-wide test ban treaty in 1963 (blue curve). Lipid age is determined by measuring ¹⁴C levels in lipids (1) and plotting this value against the bomb-curve (2) to determine the difference between the year corresponding to the atmospheric ¹⁴C concentration (3) and the biopsy collection date (dashed line). Atmospheric ¹⁴C levels are presented as ¹⁴C/¹²C ratios in units of Fraction Modern (for a definition of ‘Modern’ see Supplement 2). B: Lipid age and turnover do not change as a function of person age. Lipid age is shown for three individuals born in 1940.2, 1959.9 and 1967.9. Lipid age was shown to be the same for all individuals, despite markedly different subject ages. Fat biopsies were collected from all individuals on the same date (dashed vertical line). The solid vertical line indicates the date of birth (DOB). The small dashed lines show the ¹⁴C lipid value for each individual (only two 14C lipid values are shown, since two of them were equal).

Fig.2

Adipocyte age and lipid turnover in subcutaneous fat. A: Distribution of values for lipid age in healthy non-obese or obese individuals. B: The distribution of values for human adipocyte age. Data are obtained from a previous publication (see main text). C: Lipid age in 48 non-obese, 30 obese and 13 non-obese FCHL subjects. D: Lipid storage in the same cohort as in C. T-bars indicate standard error. Overall effect is p<0.0001 by ANOVA in C and D. Results in graphs are from post-hoc test. Data are from Cohort 1 (See Suppl. 2).

Fig. 3

Correlation between adipocyte triglyceride turnover and insulin resistance (HOMA-IR index). A linear regression analysis was performed on all individuals from cohort 1 having insulin resistance measures (n=82). HOMA-IR was correlated with lipid storage (A) and lipid age (B). The relationship between lipid age and HOMA-IR remained significant when body mass index (BMI), gender or group (non-obese, obese, FCHL) were included in the analysis (partial r=0.41, p=0.006 with BMI using multiple regression analysis and F=16.6, p=0.0001 F=4.8, p=0.03 for gender or group, respectively, using ANCOVA).

Fig. 4

Correlation between lipid turnover and adipocyte lipolysis. A and B: Lipid age and lipid removal rates with dibutyryl cyclic AMP (A,B), which is a phosphodiesterase resistant and stabile cyclic AMP analogue stimulating the protein kinase A complex; forskolin (C,D), a stimulator of adenylate cyclase which stimulates cyclic AMP production and isoprenaline (E,F), a synthetic beta adrenergic receptor-selective catecholamine acting as a lipolytic agents. Linear regression analysis was used. Data are from non-obese and obese individuals from cohort 1. Data with lipolytic agents versus lipid age were significant when analysed using body mass index as covariate in multiple regression analysis (partial r=−0.35; p≤0.004).