Researchers Crack the Conundrum of Why We Gain Weight As We Get Older

Our body weight fluctuates over our lifetime, influenced by a variety of lifestyle and biological factors. As we age, the diet or exercise regimen we adopted in our youth may not produce the same effects on our body shape, and it can become particularly difficult to maintain or lose weight. A comprehensive review published in 2013 suggests that adults gain weight progressively through middle age, with the average weight gain being 0.5 to 1kg per year. Whilst this seems only a modest amount of weight gain, it can accumulate over time and even lead to obesity.

What is fat?

There are (at least) two types of fat cells. White adipose tissue (WAT) is specialized to store energy in the form of triglycerides. Brown adipose tissue (BAT), on the other hand, is specialized to dispel chemical energy in the form of heat. WAT is the predominant form of fat in the body and has many purposes. It provides thermal insulation and "padding" for our internal organs, in addition to cushioning our bodies against external interactions with the environment. Excess white fat, however, can be detrimental.¹

Adipocytes (fat cells) are large triglyceride-filled cells that constitute over 90 % of the WAT mass. The balance between triglyceride storage and removal (known as lipid turnover) determines the overall WAT size.

As the world faces a global obesity epidemic, an increasing number of research studies are exploring the physiological mechanisms underlying lipid turnover at the molecular level. What has remained unknown is whether lipid turnover is constant over the human life span. This is primarily due to the methodological challenges associated with conducting long-term lipid turnover studies. 

Previous research has relied on short-term isotope labeling experiments or determining lipolysis (the enzymatic hydrolysis of lipids) in vitro. A longitudinal exploration is required to understand the extent by which growth, reduction or maintenance of WAT mass is regulated by lipid turnover.

In a new study published in Nature Medicine, researchers at the Karolinska Institute, in collaboration with Uppsala University and the University of Lyon , have been successful in this feat.²

Using radiocarbon dating to assess lipid age

To investigate lipid turnover across the adult life span, or following long-term substantial body weight change, the researchers performed longitudinal analyses of lipid age in human subcutaneous WAT.

The study sample comprised two cohorts: 54 individuals (10 males and 44 females) that were assessed for an average time of 13 years (ranging from 7-16 years) and a second cohort of 41 morbidly obese women followed for four to seven years post bariatric surgery.

In both cohorts, subcutaneous abdominal WAT biopsies were taken at baseline and follow-up. Subcutaneous WAT was analyzed in the study as this type of fat is more accessible and is more sensitive to lipid turnover changes.

To determine lipid age, the ₁₄C/₁₂C ratio in the lipids from the subcutaneous adipocytes was measured, a method known as radiocarbon dating. By assessing the incorporation of ₁₄C into fat cell lipids, the scientists could retrospectively calculate the age and therefore the turnover of lipids during the individual's lifetime.

Lipid turnover decreases as we age

The study results showed that in the cohort of 54 individuals, all subjects (regardless of whether they experienced weight loss or gain) demonstrated decreased lipid turnover in their fat tissue sample. Individuals that did not compensate for the reduction of lipid turnover by consuming fewer calories experienced a weight gain of 20 %, on average.

"The results indicate for the first time that processes in our fat tissue regulate changes in body weight during ageing in a way that is independent of other factors," says Peter Arner, Professor at the Department of Medicine in Huddinge at Karolinska Institute and the study's first author. "This could open up new ways to treat obesity."

In the second cohort of 41 female bariatric surgery patients, the researchers were keen to investigate how their lipid turnover rates impacted their ability to maintain weight loss for four to seven years. Interestingly, the study results illustrated that the individuals who had a low lipid turnover rate prior to the surgery were able to increase their turnover and maintain weight loss. The researchers postulate that these individuals may have had more "room" to increase their lipid turnover than those who already had a high-level pre-surgery.

"Changes in total energy expenditure and lipid oxidation have an impact on fat mass. Our study suggests that the turnover of adipose lipids is another important and independent regulator," the authors note in the paper. Previous research has suggested that one way to increase lipid turnover is to increase our exercise expenditure, and thus the study supports this notion.

Advancing our understanding of obesity

"Obesity and obesity-related diseases have become a global problem," says Kirsty Spalding, senior researcher at the Department of Cell and Molecular Biology at the Karolinska Institute and the study's last author. "Understanding lipid dynamics and what regulates the size of the fat mass in humans has never been more relevant."

A limitation noted by the authors is that the study sample was female dominated: " This study primarily investigated women and as such we cannot rule out a sex effect on lipid turnover." Thus, it may be pertinent to conduct further research in a gender-balanced sample. 

Concluding their paper, the authors say: "These results encourage the development of therapeutic and lifestyle strategies to counteract age-related decreases in lipid turnover rates and recognize the importance to adapt adipose lipid turnover for the maintenance of normal weight or weight loss. Therefore, identifying factors affecting lipid turnover could be of clinical relevance."

References:

1.     Cohen and Spiegelman. 2016. Cell biology of fat storage. Molecular Biology of the Cell. DOI: 10.1091/mbc.E15-10-0749. 

2.     Arner et al. 2019. Adipose lipid turnover and long-term changes in body weight. Nature Medicine. DOI: https://doi.org/10.1038/s41591-019-0565-5.