Cycling our way to fit fat

Abstract

Adipose tissue is increasingly being recognized as a key regulator of whole body carbohydrate and lipid metabolism. In conditions of obesity and insulin resistance mitochondrial content in this tissue is reduced, while treatment with insulin sensitizing drugs such as thiazolidinediones (TZDs) increase mitochondrial content. It has been known for decades that exercise increases mitochondrial content in skeletal muscle and now several laboratories have shown similar effects in adipose tissue. To date the specific mechanisms mediating this effect have not been fully identified. In this review we highlight recent work suggesting that increases in lipolysis and subsequently fatty acid re-esterification trigger the activation of 5' AMP-activated protein kinase (AMP) activated protein kinase and ultimately the induction of mitochondrial biogenesis. It is our current view that this pathway could be a unifying mechanism linking numerous systemic factors (catecholamines, interleukin-6, meteorin-like) to induction of mitochondrial biogenesis following exercise.

Keywords: AMPK; Adipose Tissue; PGC‐1α; exercise; mitochondria.

Figure 1

The biochemical pathways regulating lipolysis and fatty acid re‐esterification. Triglycerides are broken down to glycerol and fatty acids by the sequential actions of adipose triglyceride lipase, hormone sensitive lipase and monolglyceride lipase. Re‐esterification involves the conversion of pyruvate to glycerol‐3‐phosphate by phosphoenolpyruvate carboxykinase. This process is aided by pyruvate dehydrogenase kinase 4 which inhibits the activity of the pyruvate dehydrogenase complex, thereby shuttling pyruvate away from acetyl‐CoA and towards re‐esterification.

Figure 2

Exercise drives the breakdown of triglyceride molecules into fatty acids. Approximately half of these fatty acids are converted to acyl‐CoA by acyl‐CoA synthetase in a process that produces AMP. Increased AMP can activate AMPK, which would then drive PGC‐1α expression and stimulates mitochondrial biogenesis in AT.

Figure 3

Exercise stimulates secretion of catecholamines, interleukin‐6, and meteorin‐like (metrl). Catecholamines bind to β‐adrenergic receptors on the adipocyte to stimulate lipolysis through a PKA‐mediated pathway. IL‐6 stimulates lipolysis, though speculation remains regarding the precise mechanisms. Metrl indirectly drives lipolysis by modulating the secretion of catecholamines from adipose tissue macrophages. These factors activate lipolysis and consequently re‐esterification. This increases AMP‐activated protein kinase activity, the expression of PGC‐1ɑ and mitochondrial biogenesis. Figure clipart provided by Servier Medical Art (www.servier.com).