Logo Université Laval Logo Université Laval
International Chair on Cardiometabolic Risk
My Healthy Waist

Editorial: Regional fat distribution, fatty acid metabolism and adipocytes

By Michael Jensen, MD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA

Because body fat distribution is such a powerful predictor of the metabolic consequences of obesity, we originally sought to understand whether free fatty acid (FFA) release was different in upper body obese vs. lower body obese adults. We hypothesized that increased FFA release, as opposed to decreased clearance, might be an explanation for the metabolic abnormalities associated with upper body obesity [1]. Indeed, we found that women with upper body obesity had somewhat higher fasting plasma FFA concentrations, resulting from accelerated total body adipose tissue lipolysis [2]. We also found a major defect in the ability of insulin to suppress lipolysis in upper body obesity [2-3]. Reports of differences in lipolysis from adipocytes collected from different depots [4-6] prompted us to test whether adipose tissue lipolysis was regionally heterogeneous in vivo. To test this hypothesis we adopted the approach of employing femoral artery, femoral vein, hepatic vein catheterization combined with measurements of regional blood flow developed by Wahren [7], combined with isotope dilution techniques. Our goal was to understand whether various depots contributed differently to whole body fatty acid release. To our surprise, upper body subcutaneous fat was the source of most excess FFA in upper body obesity [8], in contrast to our hypothesis that intra-abdominal (visceral) fat was the source of most systemic FFA. We subsequently found that the inability of insulin to adequately suppress FFA release from upper body subcutaneous fat was a major defect in upper body obesity [9] and type 2 diabetes [10]. The accelerated rates of lipolysis from upper body subcutaneous fat, however, suggested to us that the gain of regional fat was not related to defective release of fatty acids but more likely related to greater storage of fatty acids.

To understand what might be the cause of preferential upper body fat gain, we adapted the technique of providing meal containing tracers followed by adipose tissue biopsies [11-12] to understand how different fat depots store dietary fatty acids. The goal was to test whether preferential meal fat storage might explain the tendency for some individuals to gain fat preferentially in one depot vs. another. Unexpectedly, both men and women are more efficient at storing dietary fat in upper body subcutaneous fat than lower body subcutaneous fat on a gram-per-gram basis [13-14], although when excess dietary fat is consumed women increase meal fat storage more so in leg fat than do men [15]. We also found that in normal weight adults, visceral fat is very efficient at storing dietary fatty acids on a per-gram basis [16], but as visceral fat mass increases, the efficiency of dietary fat stores in visceral fat decreases remarkably [17]. These results, and the finding that meal fat storage does not predict regional fat gain in response to overfeeding [18], suggested to us that regional variations in meal fat storage do not entirely account for inter-individual differences in body fat distribution. Despite our initial skepticism that adipocytes could take up FFA directly (independent of a VLDL lipoprotein lipase pathway), we performed studies to examine whether direct re-uptake of circulating FFA occurs and if it relates to body fat distribution in humans.

To our surprise, we found significant re-uptake of fatty acids in subcutaneous adipose tissue, much more so in women than in men [19]. In the postabsorptive state, approximately 9-10% of circulating FFA are restored in subcutaneous fat in normal weight women. Furthermore, in women lower body subcutaneous fat is as or more efficient at taking up FFA as is upper body subcutaneous fat [19-20]. Men take up a smaller proportion of circulating FFA (approximately 3%) [19-20], and upper body subcutaneous fat in men is more efficient than lower body subcutaneous fat in this regard [19-20]. Similar to our findings with meal fatty acid uptake, we found that direct FFA uptake in visceral fat is greater in those with small amounts of visceral fat [21], and this relates strongly to high amounts of factors that promote fatty acid storage (CD36, acyl-CoA synthetase, and diacylglycerol acyltransferase) in small visceral adipocytes compared to large visceral adipocytes.

Not all of regional fat gain can be attributed to balances between uptake and release of fatty acids in pre-existing adipocytes. Because adipocytes have an upper size limit, we hypothesized that at some point in fat gain, adults must create new adipocytes. To test this hypothesis we overfed 28 normal weight adult men and women to gain ≈4 kg of fat, measuring fat cell size and number in the abdomen and thigh before and after fat gain [22]. We found that fat gain in the abdomen was largely due to increases in fat cell size whereas fat gain in the lower body was due to increases in fat cell number [22]. The average gain of lower body fat of 1.6 kg was due to the gain of ≈2.6 billion new adipocytes in the course of 8 weeks. Those who gain the most leg fat, and therefore the greatest number of new fat cells, gained the least upper body and visceral fat [22].

In summary, abnormal insulin regulation of FFA release from upper body subcutaneous fat is a major defect in people with upper body fat distribution, exposing liver, heart, skeletal muscle and pancreatic islets to higher than normal FFA concentrations during postprandial hyperinsulinemia. This defect likely contributes to many of the metabolic abnormalities seen with upper body obesity. Regional differences in fat gain may be related to inter-individual differences in the ability of preadipocytes to be recruited to become new, mature adipocytes. Although we have a better understanding of the genesis of regional fat gain and the factors that modulate body fat distribution, we do not yet understand the remarkable abnormalities in insulin suppression of lipolysis in upper body obesity.

References

  1. Evans DJ, Hoffmann RG, Kalkhoff RK, et al. Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metabolism 1984; 33: 68-75. PubMed ID: 6361449
  2. Jensen MD, Haymond MW, Rizza RA, et al. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest 1989; 83: 1168-73. PubMed ID: 2649512
  3. Roust LR and Jensen MD. Postprandial free fatty acid kinetics are abnormal in upper body obesity. Diabetes 1993; 42: 1567-73. PubMed ID: 8405696
  4. Richelsen B, Pedersen SB, Moller-Pedersen T, et al. Regional differences in triglyceride breakdown in human adipose tissue: effects of catecholamines, insulin, and prostaglandin E2. Metabolism 1991; 40: 990-6. PubMed ID: 1895966
  5. Arner P. Role of antilipolytic mechanisms in adipose tissue distribution and function in man. Acta Med Scand Suppl 1988; 723: 147-52. PubMed ID: 2839956
  6. Leibel RL and Hirsch J. Site- and sex-related differences in adrenoreceptor status of human adipose tissue. J Clin Endocrinol Metab 1987; 64: 1205-10. PubMed ID: 3571424
  7. Hagenfeldt L, Wahren J, Pernow B, et al. Uptake of individual free fatty acids by skeletal muscle and liver in man. J Clin Invest 1972; 51: 2324-30. PubMed ID: 4639017
  8. Martin ML and Jensen MD. Effects of body fat distribution on regional lipolysis in obesity. J Clin Invest 1991; 88: 609-13. PubMed ID: 1864970
  9. Guo Z, Hensrud DD, Johnson CM, et al. Regional postprandial fatty acid metabolism in different obesity phenotypes. Diabetes 1999; 48: 1586-92. PubMed ID: 10426377
  10. Basu A, Basu R, Shah P, et al. Systemic and regional free fatty acid metabolism in type 2 diabetes. Am J Physiol Endocrinol Metab 2001; 280: E1000-6. PubMed ID: 11350782
  11. Björntorp P, Berchtold P, Holm J, et al. The glucose uptake of human adipose tissue in obesity. Eur J Clin Invest 1971; 1: 480-5. PubMed ID: 5121738
  12. Marin P, Rebuffé-Scrive M and Björntorp P. Uptake of triglyceride fatty acids in adipose tissue in vivo in man. Eur J Clin Invest 1990; 20: 158-65. PubMed ID: 2112480
  13. Romanski SA, Nelson RM and Jensen MD. Meal fatty acid uptake in adipose tissue: gender effects in nonobese humans. Am J Physiol Endocrinol Metab 2000; 279: E455-62. PubMed ID: 10913047
  14. Uranga AP, Levine J and Jensen M. Isotope tracer measures of meal fatty acid metabolism: reproducibility and effects of the menstrual cycle. Am J Physiol Endocrinol Metab 2005; 288: E547-55. PubMed ID: 15507534
  15. Votruba SB and Jensen MD. Sex-specific differences in leg fat uptake are revealed with a high-fat meal. Am J Physiol Endocrinol Metab 2006; 291: E1115-23. PubMed ID: 16803856
  16. Jensen MD, Sarr MG, Dumesic DA, et al. Regional uptake of meal fatty acids in humans. Am J Physiol Endocrinol Metab 2003; 285: E1282-8. PubMed ID: 12915396
  17. Votruba SB, Mattison RS, Dumesic DA, et al. Meal fatty acid uptake in visceral fat in women. Diabetes 2007; 56: 2589-97. PubMed ID: 17664244
  18. Votruba SB and Jensen MD. Short-term regional meal fat storage in nonobese humans is not a predictor of long-term regional fat gain. Am J Physiol Endocrinol Metab 2012; 302: E1078-83. PubMed ID: 22338076
  19. Shadid S, Koutsari C and Jensen MD. Direct free fatty acid uptake into human adipocytes in vivo: relation to body fat distribution. Diabetes 2007; 56: 1369-75. PubMed ID: 17287467
  20. Koutsari C, Ali AH, Mundi MS, et al. Storage of circulating free fatty acid in adipose tissue of postabsorptive humans: quantitative measures and implications for body fat distribution. Diabetes 2011; 60: 2032-40. PubMed ID: 21659500
  21. Ali AH, Koutsari C, Mundi M, et al. Free fatty acid storage in human visceral and subcutaneous adipose tissue: role of adipocyte proteins. Diabetes 2011; 60: 2300-7. PubMed ID: 21810594
  22. Tchoukalova YD, Votruba SB, Tchkonia T, et al. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc Natl Acad Sci U S A 2010; 107: 18226-31. PubMed ID: 20921416