COMMENTARIES

Does Impaired Adipose Tissue Lipid Storage Contribute to Metabolic Diseases?

Viswanathan Saraswathi and Alyssa H. Hasty, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232
Please address correspondence to:
Alyssa H. Hasty
Department of Molecular Physiology and Biophysics
Vanderbilt University Medical Center
702 Light Hall
Nashville, TN 37232-0615
Tel: 615-322-5177
E-mail: alyssa.hasty@vanderbilt.edu

Introduction

Obesity is a key feature of metabolic syndrome, which greatly predisposes individuals to cardiovascular disease, type 2 diabetes, and numerous cancers, and is associated with markedly diminished life expectancy [1]. Nevertheless, not all obese individuals develop metabolic syndrome or insulin resistance. Published evidence suggests that about 20% of obese individuals have a normal metabolic profile and insulin sensitivity [2]. Obesity-associated complications, in particular insulin resistance, are predominantly mediated by disordered lipid partitioning resulting in ectopic lipid deposition in peripheral organs such as muscle and liver [3,4]. However, it has also been reported that obese individuals may not always accumulate triglycerides in peripheral organs [5]. Therefore, it is increasingly recognized that total body fat is not the sole source of the adverse health complications of obesity; rather, an emerging paradigm supports the view that obesity-associated complications are not due to increased fat mass per se, but to an altered lipid partitioning between adipose and non-adipose tissues [6,7].

 
Adipose Tissue as a Storage and Secretory Organ

Adipose tissue plays an important role in lipid homeostasis by storing excess energy in the form of triglyceride. Insulin promotes lipid storage in adipose tissue by suppressing lipolysis, thus regulating the release of free fatty acids. Impairment of adipose tissue storage function, as seen in both obesity and lipoatrophic conditions, is associated with the accumulation of ectopic triglycerides in the liver and skeletal muscles [8,9]. In addition to functioning as a storage organ, adipose tissue also secretes many bioactive proteins called adipokines, which play an important role in regulating energy homeostasis, lipid metabolism, and inflammatory events. Notably, some of these adipose tissue secreted factors, such as leptin and adiponectin, have the ability to influence lipid metabolism not only locally in the adipose tissue but also in the liver and muscle.

 
Adipokines and Ectopic Lipid Accumulation

Leptin, the product of the ob gene, is a peptide hormone that is produced primarily by adipose tissue and has been shown to regulate food intake and energy expenditure. In addition to its central effects, leptin is capable of interacting with numerous peripheral tissues expressing the leptin receptor, including skeletal muscle, liver, and pancreas. Muoio et al. [10] have demonstrated that leptin stimulates fatty acid oxidation while simultaneously decreasing the incorporation of fatty acids into the intramuscular triglyceride pool in murine muscle. This effect of leptin on fatty acid oxidation in muscle is mediated, at least in part, by the activation of AMP-activated protein kinase (AMPK) [11]. Leptin can reduce lipid accumulation not only in muscle, but also in liver [12,13] and pancreas [14].

          Adiponectin is the most widely studied, pleiotropic adipokine having several known beneficial actions which include reducing inflammatory cytokine production, increasing insulin sensitivity, and protecting against atherosclerotic lesion formation [15,16]. Accumulating evidence suggest that similar to leptin, adiponectin can also promote fatty acid oxidation and reduce ectopic lipid accumulation in non-adipose tissues [17,18]. As with leptin, activation of AMPK is involved in mediating the effect of adiponectin on fatty acid oxidation in these tissues.

 
Adipokines and Lipid Storage in Adipose Tissue

While several lines of evidence underscore the role of fatty acid oxidation in preventing triglyceride accumulation in non-adipose tissues, an interesting question arises as to whether ectopic lipid deposition can also be prevented by promoting fat storage in adipose tissue. Moreover, it is still unclear whether adipose tissue secreted factors may have a role in modulating lipid accumulation in adipose tissue itself. An elegant study by Kim and colleagues has demonstrated that overexpression of adiponectin in adipose tissue leads to a significant increase in adipocyte cell number and hence to an overall expansion of adipose tissue mass in mice [19]. More importantly, the increased adiposity in these mice was associated with an improved metabolic profile as evidenced by reduced plasma triglycerides, free fatty acids, glucose and insulin, and improved glycemic control. While this is the first report addressing the direct effects of adiponectin on adipose tissue expansion, certain pharmacological agents and dietary factors that can increase adiponectin levels have also been shown to increase adiposity.


Therapeutic and Nutraceutic Regulation of Lipid Storage in Adipose Tissue

It has been known for some time that thiazolidinediones, a class of drugs that activate peroxisome proliferator-activated receptor (PPAR)g, lead to peripheral adipose tissue mass expansion while improving insulin sensitivity [20]. Moreover, PPARg agonists have also been shown to reduce ectopic lipid accumulation in liver and muscle [21,22]. With regards to dietary interventions, Ide has reported an increase in adipose tissue mass in ICR mice fed high sucrose diet supplemented with fish oil [23]. In this study, an increased fat mass in mice upon fish oil feeding was associated with reduced lipid accumulation in liver and improved insulin sensitivity. We have also demonstrated that fish oil feeding increases adipose tissue mass in low density lipoprotein receptor-deficient mice. Despite the increase in adipose tissue mass, there was reduced inflammatory cytokine expression in the adipose tissue. Furthermore, this increased fat mass was associated with reduced hepatic steatosis, improved plasma lipid profiles, and decreased atherosclerotic lesion formation [24]. It is also interesting to note that both PPARg agonists and fish oil have been consistently shown to increase plasma adiponectin levels [24-27]. Thus, it is tempting to speculate that adiponectin, and agents that increase adiponectin concentrations, can improve metabolic profiles by directing lipid partitioning to adipose tissue rather than other peripheral organs.

 
Summary

Obesity is an important feature of the metabolic syndrome leading to insulin resistance, type 2 diabetes, and atherosclerosis. However, a novel paradigm suggests that it is the distribution of triglycerides, rather than the total amount of adipose tissue, that affects the risk of metabolic disorders. Emerging literature on the effect of pharmacological agents and dietary factors suggests that the expansion of adipose tissue mass can be beneficial under certain conditions. Finally, adiponectin, induced by these interventions, may promote lipid storage in adipose tissue, thus protecting other organs and cells from the deleterious effects of lipid deposition.

References

  1.    Haslam DW, James WP. Obesity. Lancet 2005;366:1197-1209.
  2.    Karelis AD, St-Pierre DH, Conus F, Rabasa-Lhoret R, Poehlman ET. Metabolic and body composition factors in subgroups of obesity: what do we know? J Clin Endocrinol Metab 2004;89:2569-75.
  3.    Weiss R, Dufour S, Taksali SE, et al. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 2003;362:951-57.
  4.    Tiikkainen M, Tamminen M, Hakkinen AM, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res 2002;10:859-67.
  5.    Weiss R, Taksali SE, Dufour S, et al. The "obese insulin-sensitive" adolescent: importance of adiponectin and lipid partitioning. J Clin Endocrinol Metab 2005;90:3731-37.
  6.    Weiss R. Fat distribution and storage: how much, where, and how? Eur J Endocrinol 2007;157(Suppl.1):S39-45.
  7.    Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004;89:463-78.
  8.    Rasouli N, Molavi B, Elbein SC, Kern PA. Ectopic fat accumulation and metabolic syndrome. Diabetes Obes Metab 2007;9:1-10.
  9.    Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004;28(Suppl.4):S12-21.
  10.    Muoio DM, Dohm GL, Fiedorek FT, Jr., Tapscott EB, Coleman RA. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 1997;46:1360-63.
  11.    Minokoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339-43.
  12.    Huang W, Dedousis N, O'Doherty RM. Hepatic steatosis and plasma dyslipidemia induced by a high-sucrose diet are corrected by an acute leptin infusion. J Appl Physiol 2007;102:2260-65.
  13.    Huang W, Dedousis N, Bandi A, Lopaschuk GD, O'Doherty RM. Liver triglyceride secretion and lipid oxidative metabolism are rapidly altered by leptin in vivo. Endocrinology 2006;147:1480-87.
  14.    Unger RH, Zhou YT. Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 2001;50(Suppl.1):S118-121.
  15.    Nishida M, Funahashi T, Shimomura I Pathophysiological significance of adiponectin. Med Mol Morphol 2007;40:55-67.
  16.    Lara-Castro C, Fu Y, Chung BH, Garvey WT Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease. Curr Opin Lipidol 2007;18:263-70.
  17.    Tomas E, Tsao TS, Saha AK, et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A 2002;99:16309-13.
  18.    Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003;112:91-100.
  19.    Kim JY, van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007;117:2621-37.
  20.    Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2004;89:4312-19.
  21.    Tiikkainen M, Hakkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen H. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004;53:2169-76.
  22.    Rasouli N, Raue U, Miles LM, et al. Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Am J Physiol Endocrinol Metab 2005;288:E930-934.
  23.    Ide T. Interaction of fish oil and conjugated linoleic acid in affecting hepatic activity of lipogenic enzymes and gene expression in liver and adipose tissue. Diabetes 2005;54:412-23.
  24.    Saraswathi V, Gao L, Morrow JD, Chait A, Niswender KD, Hasty AH. Fish oil increases cholesterol storage in white adipose tissue with concomitant decreases in inflammation, hepatic steatosis, and atherosclerosis in mice. J Nutr 2007;137:1776-82.
  25.    Boyle PJ. Diabetes mellitus and macrovascular disease: mechanisms and mediators. Am J Med 2007;120:S12-17.
  26.    Rossi AS, Lombardo YB, Lacorte JM, et al. Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats. Am J Physiol Regul Integr Comp Physiol 2005;289:R486-R494.
  27.    Neschen S, Morino K, Rossbacher JC, et al. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes 2006;55:924-28.

 

 

CLOSE THE WINDOW