Previous research by Lam et al., (2005) was focused on hypothalamus sensing of fatty acids and lipoproteins and its role in pathopyshiology. They found that it was possible to have a large effect on lipid homeostasis by injecting glucose as well as lactate in the 3rd cerebral ventricle. Altering hypothalamic sensing of circulating lipids could disrupt glucose homeostasis throughout the body by decreasing oleic acid levels in the liver.

The monounsaturated fatty acid oleic acid plays a significant role in stimulating lipid addition to nascent VLDL particles in the liver. The presence of oleic acid can be reduced by the infusion of glucose or lactate into the hypothalamus. By examining the effects of central glucose levels on lipid homeostasis, Lam et al., (2007), determined that decreasing the activity of SCD1 in the liver was adequate to lower the hepatic levels of oleyl-CoA.

The effects on SCD1 activity of increasing glucose concentration in the hypothalamus by 70%:

•Glucose did not alter levels of plasma fatty acids, However, it did noticeably reduce circulating levels of triglycerides.

•The central administration of glucose in the hypothalamus decreased the levels of plasma triglycerides by limiting secretion of triglyceride-rich VLDL.

•Glucose markedly decreased the secretion of large triglyceride-rich VLDL.

The effects on SCD1 activity of increasing lactate concentration to 5mM:

• Similar to the results with glucose, lactate did not decrease plasma free fatty acids but did significantly reduce plasma triglyceride levels.

•An increase in lactate decreased both plasma triglyceride levels and VLDL secretion.

Monitoring metabolism of glucose until the final VLDL secretion . Inhibitors had to be included in the project in order to understand the complexities of brain glucose metabolism. To determine whether metabolism of lactate to pyruvate is an essential biochemical step in astrocytes, an inhibitor of the enzyme LDH was injected. Also, glibenclamide, an inhibitor of the ATP-sensitive potassium channels, was injected to determine if the channels were essential to fat synthesis.

•The results of the infusions had the same effect. The results of glucose and lactate were both abolished by introducing the LDH inhibitor as well as glibenclamide. Secretion of plasma triglycerides from the liver returned to its normal level, signaling the importance of the central glucose levels in the hypothalamus on metabolism. The process of converting lactate to pyruvate opens an ATP channel-dependent pathway is essential for a decrease in secretion levels of VLDL.

The administration of glucose and lactate lowered the amount of triglyceride levels (Figure 13). There is a marked decrease in basal levels of plasma triglycerides compared to preinfusion levels.

Figure 13: [Figure 1b, Lam, et al., 2007]

Coinfusing the LDH inhibitor as well as the ATP-sensitive potassium channels negated the effects of glucose and lactate injections (Figure 14). The plasma triglyceride levels were similar in concentration to preinfusion levels.

Figure 14: Experimental Results [Figure 1c, Lam, et al., 2007]

Glucose was able to decrease the size of the VLDL particles that were being excreted as determined by nuclear magnetic resonance (NMR) (Figure 15). Over a period of 160 minutes, the plasma large VLDL particle decreased from approximately 60nM to 38 nM.

Figure 15: [Figure 2d, Lam, et al., 2007]

Glucose decreased the levels of triglycerides in VLDL as determined by fast performance liquid chromatography (FPLC) (Figure 16). The glucose levels were compared to mannitol levels as well as a pre-infusion vehicle.

Figure 16: Experimental Results [Figure 2e, Lam, et al., 2007]