Effect of plasma triglyceride metabolism on lipid storage in adipose tissue: studies using genetically engineered mouse models.
The obesity epidemic is associated with an increased incidence of type 2 diabetes, cardiovascular morbidity and various types of cancer. A better insight into the molecular mechanisms that underlie adipogenesis and obesity may result in novel therapeutic handles to fight obesity and these associated diseases. Adipogenesis is determined by the balance between uptake of fatty acids (FA) from plasma into adipocytes, intracellular FA oxidation versus esterification of FA into triglycerides (TG), lipolysis of TG by intracellular lipases, and secretion of FA from adipocytes. Here, we review the mechanisms that are specifically involved in the entry of FA into adipose tissue. In plasma, these originating FA are either present as TG within apoB-containing lipoproteins (i.e. chylomicrons and VLDL) or as free FA bound to albumin. Kinetic studies, however, have revealed that TG are the major source of FA entering adipose tissue, both in the fed and fasted condition. In fact, studies with genetically engineered mice have revealed that the activity of lipoprotein lipase (LPL) is a major determinant for the development of obesity. As a general rule, high fat diet-induced adipogenesis is aggravated by stimulated LPL activity (e.g. by adipose tissue-specific overexpression of LPL or deficiency for apoCIII), and attenuated by inhibited LPL activity (e.g. by adipose-specific deficiency for LPL, overexpression of apoCI or angptl4, or by deficiency for apoE or the VLDL receptor). In addition, we describe that the trans-membrane transport of FA and cytoplasmic binding of FA in adipocytes can also dramatically affect adipogenesis. The relevance of these findings for human pathophysiology is discussed.
Voshol
Peter J
PJ
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
Rensen
Patrick C N
PC
van Dijk
Ko Willems
KW
Romijn
Johannes A
JA
Havekes
Louis M
LM
D050156:Adipogenesis; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001692:Biological Transport; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014280:Triglycerides / Q000097:blood*
D001055:Apolipoproteins B; D005227:Fatty Acids; D014280:Triglycerides; D008071:Lipoprotein Lipase