The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 7 No.
4 • September 2004
High-Dose Alpha-Lipoic Acid Has Antiobesity Effects in Rats
A new study reports that high-dose (supraphysiological) alpha-lipoic acid suppresses hypothalamic AMP-kinase, a nutrient sensor and food-intake regulator, resulting in antiobesity effects.
AMP-activated protein kinase (AMPK) has recently been identified as a nutrient sensor, the activity of which is inhibited by exposure to anorexigenic (feeding-inhibitory) signals, such as leptin, insulin, high glucose, and refeeding (after fasting). The inhibition of AMPK is, in fact, necessary for leptin’s effects on food intake and body weight, and failure of leptin to suppress AMPK is a cause of leptin resistance. AMPK is also reported to be increased by stress. The enzyme regulates energy metabolism by inhibiting energy-consuming pathways and inducing pathways that generate ATP. It enhances feeding (orexigenic) signals in the fasting state, while low AMPK signaling results in suppression of feeding under ad libitum conditions. Hence, suppression of AMPK in the hypothalamus is a potential way to inhibit feeding by mimicking a fully fed condition.
The new study reports that, in Sprague-Dawley rats treated with intraperitoneal or intracerebroventricular injections or high doses of oral alpha-lipoic acid (what would amount to about 2.5 g per day in an adult human), hypothalamic AMPK is suppressed, with decreases in food intake and weight loss. Results showed that the treated rats had increased energy expenditure compared to controls and that there was an increase in the uncoupling protein-1 (Ucp-1), which is associated with increased energy expenditure and reduced oxidative stress. One interpretation of these results is that the increased levels of Ucp-1 increase overall energy expenditure by oxidizing fat stores. The oral doses of alpha-lipoic acid received by the Sprague-Dawley rats in the study were 0.25%, 0.5%, and 1% by weight in rat chow. The rats receiving 0.25% alpha-lipoic acid showed a trend toward reduced body weight that was, however, not significant at P<0.05. Reduced weight in rats getting 0.5% and 1% alpha-lipoic acid was significant at this level. Hence, rats receiving 0.5% wt/wt of alpha-lipoic acid would amount to about 2.5 g of the substance per day in a human consuming 500 g (dry weight) of food. The authors suggest that, since alpha-lipoic acid is known to stimulate glucose transport and ATP synthesis in peripheral tissues, it may decrease hypothalamic AMPK activity by increasing glucose uptake, glucose metabolism, or both in the hypothalamus.
Tests on the treated mice showed no toxicity or illness in relation to food intake or organ pathology, and animals had unchanged blood-cell counts and blood chemistry.
2.5 g per day of alpha-lipoic acid for a human is a very high dose and is definitely supraphysiologic (far beyond any conceivable dietary intake). Though the mice had no obvious toxicity, humans may metabolize such large amounts of alpha-lipoic acid differently. Originally, the nutrient was investigated as an antidote to certain mushroom poisonings in humans. It was very effective, but at doses of 6–8 g per day, decreased survival resulted, with liver mitochondrial damage. Hence, any experimentation with high-dose alpha-lipoic acid is just that, an experiment, and is therefore best done under the close supervision of a nutritionally expert physician. Durk is currently experimenting with 2 g of alpha-lipoic acid per day and has found it helpful in reducing his weight. Sandy is taking 1.25 g of alpha-lipoic acid daily.
- Min-Seon Kim et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nature Med 10(7):727-33 (2004).
- Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004 Apr 1;428(6982):569-74.
- Small et al. Cellular energy sensor balances the scales. Nature Med 10(7):681-2 (2004).
- Watt MJ, Steinberg GR, Chan S, Garnham A, Kemp BE, Febbraio MA.Beta-adrenergic stimulation of skeletal muscle HSL can be overridden by AMPK signaling. FASEB J 2004;18(12):1445-6. Epub 2004 Jul 01.
- This study didn’t report the effects of alpha-lipoic acid on AMPK in skeletal muscle. However, experimental evidence indicates that AMPK has opposite effects in peripheral tissues; for example, leptin activates AMPK in skeletal muscle, whereas it inactivates AMPK in the hypothalamus. In muscle, AMPK exerts an antilipolytic effect that may override the lipolytic effect of adrenaline. Authors of another recent study note that AMPK is activated in skeletal muscle by an increase in energy expenditure, as in exercise, and by lack of fuel, leading to (among other things) an increase in fatty acid oxidation. The same paper also reported that AICAR, an inducer of AMPK, inhibited oxidative stress and NFkappaB activation resulting from hyperglycemia in incubated HUVECs (human umbilical-vein endothelial cells). The authors describe a recent study in which the diabetes drug metformin was shown to activate AMPK in skeletal muscle of patients treated with the drug. Moreover, they mention a recent finding that adiponectin, a hormone released by fat cells that increases insulin sensitivity in experimental animals, also activates AMPK in skeletal muscle. See Yamauchi et al, “Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase,” Nature Med 8(11):1288-95 (2002). This was a mouse study.
- Ruderman et al. Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes. Biochem Soc Trans 31(Pt 1):201-6 (2003).