Cell Culture: New Year's Diets

Many dieters looking to drop a quick 5 lbs will turn to the tried-and-true Aktin’s Diet. First described almost 50 years ago, the Aktin’s Diet purportedly ‘‘turns your body into a fat-burning machine’’ by severely restricting the intake of sugars and starches. Indeed, numerous animal studies indicate that low-carbohydrate, high-fat diets, such as Aktin’s, induce weight loss by triggering a shift from carbohydrate metabolism to fat oxidation. What orchestrates this metabolic switch? The mammalian brain can’t metabolize fat. Thus, as blood sugar and insulin levels plummet during an Aktin’s diet, the liver starts to generate an alternative fuel— ketones. Fatty acids are released from adipose tissue and oxidized in the liver to the ketones acetoacetate and hydroxybutrate. Using microarray analysis, Badman et al. found that a strict Aktin’s-like diet increases expression of the fibroblast growth factor 21 (FGF21) by >25-fold in livers of mice. Disrupting this hormone-like signal blocks ketogenesis and dramatically raises levels of lipid and cholesterol in the blood. Simultaneously, Inagaki et al. demonstrated that overexpressing FGF21 boosts ketogenesis by 5-fold, decreases insulin levels, and stimulates lipid breakdown in adipose tissue. Both studies identified the nuclear receptor PPARa as the activator of FGF21 transcription in the liver during fasting or low-carbohydrate, high-fat diets. Together, these findings suggest that Aktin’s-like diets work by mimicking a state of starvation. Remarkably, ‘‘ketogenic diets,’’ such as the Aktin’s, are effective at treating drug-resistant epilepsy, and 30% of patients become seizure free on this regime. Although the precise mechanisms underlying this effect are still unknown, a study by Ma et al. (2007) found that ketones reduce the firing of GABAergic neurons by opening ATP-sensitive potassium channels at the cell surface. The authors propose that ketones decrease ATP levels at the plasma membrane because they are oxidized in mitochondria but not in the cytosol as glucose is. Inagaki, T., et al. (2007). Cell Metab. 5, 415–425. Badman, M.K., et al. (2007). Cell Metab. 5, 426–437. Ma, W., et al. (2007). J. Neurosci. 27, 3618–3625.