Investigating adipose tissue turnover in humans using radiocarbon dating

Abstract

Obesity, defined as an excessive accumulation of body fat, is considered one of the major health challenges facing the world today. Adipocyte and lipid turnover determine the number and the size of fat cells, respectively. Therefore, understanding the dynamics of adipocyte and lipid turnover will provide important insights into the factors regulating the size of the fat mass. Adipose tissue is not uniformly distributed throughout the body, and the regional differences in turnover may contribute to the link between body fat distribution and increased risk of metabolic complications. Several factors such as sex and age are also known to impact fat accumulation, however, their influence on adipose tissue turnover dynamics are unclear. In this thesis, we provide a comprehensive analysis of age and turnover dynamics of both adipocytes and lipids in human subcutaneous (scWAT) and visceral (vWAT) adipose tissue, by measuring the integration of 14C derived from nuclear bomb tests into genomic DNA and lipids, across the lifespan. The effects of fat mass distribution, sex, age and BMI were investigated for their influence on adipose tissue turnover, as well as interventions such as weight loss over time.

In Paper I, we examined the differences in lipid turnover in scWAT and vWAT in individuals with a range of BMIs. While scWAT lipid age and storage capacity were increased in overweight and obese individuals, lipid age in vWAT was increased only in the excessively obese individuals and was associated with a reduced lipid removal rate. Moreover, in central or visceral obese individuals, lipid turnover was selectively increased in vWAT. Metabolically unhealthy obese individuals with small scWAT adipocytes exhibited reduced lipid turnover. In conclusion, excess body fat mass results in a depot-specific reduction in lipid turnover. Increased lipid turnover in vWAT and/or decreased lipid turnover in scWAT may contribute to metabolic complications of overweight or obesity.

In Paper II, we explored lipid turnover dynamics in adults who were followed for up to 16 years (mean follow-up time 13 years) or 5 years following significant weight loss. Lipid removal rate decreased with aging, and a failure to reciprocally adjust for lipid uptake rate resulted in weight gain. Substantial weight loss was primarily driven by a reduced rate of lipid uptake. Surprisingly, individuals with a low baseline lipid removal rate were more likely to maintain the weight loss 5 years following weight-loss surgery. Taken together, these findings identify lipid turnover as an important regulator of long-term obesity development and weight loss maintenance.

In Paper III, we compared the age of adipocytes and lipid in human scWAT and vWAT. vWAT adipocytes were found to be older than scWAT adipocytes, suggesting regional differences in the adipocyte death rate. Subject sex, age and body fat mass also had a significant impact on adipocyte age. Females had a slower death rate of adipocytes than males, and age and BMI inversely correlated with the adipocyte death rate. Lipid removal rate was also found to be lower in females than males, and decreased with aging in both depots. In summary, these results identify adipocyte and lipid removal rates as important factors contributing to regional differences in fat distribution, and that sex, age and BMI-dependent differences in turnover dynamics influence one’s risk developing obesity-associated metabolic complications.

Taken together, this thesis provides a deeper characterization of adipocyte and lipid age and turnover dynamics in humans. Furthermore, it highlights regional differences in adipocyte and lipid turnover and the important link to total fat mass accumulation and distribution, in both lean and obese individuals, females and males, and the young and the elderly.