WAT and energy homeostasis

One of the primary functions of WAT is to store excess energy as lipids, which are then mobilized to other tissues in response to metabolic needs during periods of food scarcity (9).

After copious meals, and in periods of food abundance, the adipose tissue stores the energy ingested in excess as triglycerides (TG) (Fig 2A). The adipocyte is able to accumulate astonishingly high amounts of TG, which can be stored anhydrously within intracellular lipid droplets coated with proteins called perilipins, without causing cellular lipotoxicity (26,27).

Starvation induces the breakdown of these TG into free fatty acids (FFA) and glycerol, which are released into the circulation (Fig 2B). FFA then serves as fuel for metabolically active tissues such as the skeletal muscle where their oxidation to carbon dioxide and water generates ATP.

In the liver, most of the acetyl CoA produced by FFA oxidation is used to synthesize ketone bodies (acetoacetate; β-hydroxybutyrate) released into the circulation and used as fuels by the peripheral tissues. The glycerol generated by TG hydrolysis serves for the synthesis of glucose, which is reserved for cells depending on it as an energy source (neurons, red blood cells), or participates in the hepatic production of TG (28). These TG are then packaged within very low density lipoproteins (VLDL) and released into the circulation from where they can return to WAT. Regulation of the TG stocks is crucial for survival, since without WAT and its lipid reserve, animals would have to eat continuously, which is obviously not possible. For well-known reasons, food intake occurs only in distinct episodes underscoring the importance of a control of lipid production or intake, storage, and utilization.

Regulation of lipid metabolism in adipocytes is controlled at three levels: fatty acid uptake, lipogenesis and lipolysis. Each of these processes is controlled by extracellular stimuli including insulin, corticoids, catecholamines, natriuretic peptides, and cytokines such as TNF-α, whose levels depend on conditions such as age, gender, physical activity, and nutritional factors (29). In addition, there are marked differences between the vis and sc adipose tissues in the regulation and levels of lipid metabolic activities. For instance, nearly 80% of fat is in the sc tissue, but the lipolytic effect of catecholamines is more pronounced in the vis fat whereas the antilipolytic effect of insulin is stronger in the sc fat (22).

INTRODUCTION-Adipose tissue : the organ and its functions

The adipose tissue participates in the regulation of glucose homeostasis, which depends on the action of other organs as well (pancreas, liver, brain) (29). Firstly, it is involved in glucose disposal, which provides the substrate for the de novo synthesis of fatty acids and glycerol, and thus of lipogenesis, via the glycolytic pathway. Too little or too much adiposity are associated with hyperglycemia and insulin resistance. Not surprisingly, by liberating FFA into the circulation, the adipose tissue influences insulin sensitivity and thus glucose metabolism, in the muscles and liver. Furthermore, among other functions FFA serve as a substrate for lipoprotein assembly in the liver, regulate insulin production in the pancreas, and bind to and activate the transcription factors Peroxisome Proliferator Activated Receptors (PPARs) in all tissues, which in turn results in gene expression changes and their consequences (see below) (11,29-31). Thus WAT, by being involved in the regulation of lipid and glucose metabolism, not only in adipocytes, but also in the whole body, plays an important integrative role in energy homeostasis especially in extreme conditions when food is available on a very irregular basis and/or is of variable nutritional quality.

In mammals, when excess energy is not directed correctly into sc fat, it will preferentially accumulate in vis WAT, with deleterious effects, a condition often associated with a genetic susceptibility to visceral fat obesity, and/or an endocrine-related maladaptive response to stress or smoking (32).

When the adipose tissue is deficient, for instance because it is insulin resistant, or is abnormally distributed (lipodystrophy), the extra TG will be deposited ectopically in muscle, liver and heart, and to some extent also in the pancreas, which will be detrimental to the normal functioning of these now abnormally lipid-loaded tissues. This will impact on whole body metabolism with the development of metabolic syndrome features as a consequence (Fig 3) (32).

A

Figure 2. Role of the white adipose tissue (WAT) and peripheral organs in postprandial (A) and fasting (B) states. A) In the postprandial state, the ingested nutrients reach the circulation in the form of triglycerides (in chylomicrons as very low density lipoproteins (VLDL), glucose and amino acids. In this state the main metabolic activities are the oxidation of glucose for the production of ATP in most cells, and the storage of excess fuel molecules in adipocytes as triglycerides, in hepatocytes as proteins, glycogen and triglycerides, and in skeletal muscle fibers as proteins and glycogen. In fuel excess conditions, amino acid oxidation increases in proportion to increments in protein intake, regardless of carbohydrate and fat substrate availability.

B

Figure 2. Role of the white adipose tissue (WAT) and peripheral organs in postprandial (A) and fasting (B) states. B) Fasting induces breakdown of the triglycerides from WAT into free fatty acids and glycerol, both released into the circulation. Free fatty acids can be directly oxidized by skeletal muscle fibers for the production of ATP. Hepatocytes use glycerol for gluconeogenesis, and free fatty acids for ketone body synthesis. Both glucose and ketone bodies are important fuel molecules for the peripheral organs. In fuel shortage conditions, the extent to which amino acid oxidation rises above the minimum required rate depends on the proportion of the energy needs, which is covered by free fatty acids (FFA), glucose and ketone body oxidation. Stored molecules (Triglycerides, Glycogen, Proteins are in indicated in bold capitals.) Adapted in part from (33).