Macronutrient-sensing mechanisms in the brain

Linda Benedict, Martin, Roy J, Keenan, Michael J.  |  11/25/2008 9:22:28 PM

Figure 1. The macronutrients inhibit the expression of NPY and AGRP, two of the most powerful brain signals for feeding. The same macronutrients also stimulate POMC and CART, the primary brain signals for stopping feeding behavior.

Roy J. Martin, Michael J. Keenan, Christopher Morrison and Jun Zhou

The major nutrition-related disease in Louisiana is obesity. Obesity is a result of overconsumption of food relative to energy expenditure. Protein, carbohydrate and fat are calorie-containing components of food. They also are called dietary macronutrients. Research at the LSU AgCenter is focused on how the brain senses macronutrients and how this sensing leads to a change in the control of appetite and obesity. This research has identified important links between nutrient sensing and the mechanisms by which this sensing alters the expression of neuronal genes related to hunger and satiety. The knowledge is essential to identify bioactive food components that suppress hunger-signaling after weight loss.

Eating behavior
People, as well as animals, usually overeat after food restriction. This is a good example of how eating behavior is linked to the body’s metabolic requirements. The brain is the major integrator of metabolic signals generated from peripheral tissue, such as muscle and fat. Certain brain areas can "sense" the nutrient status, or metabolic requirement, of peripheral tissues and regulate eating behavior correspondingly. Such regulation is achieved through changes in particular expression of neuropeptides – peptides (or compounds formed from two or more amino acids) that influence activity in the brain. Current, well-established neuropeptides that directly regulate eating behavior are neuropeptide Y (NPY), Agouti-related peptide (AgRP), Pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART).

LSU AgCenter researchers are studying how these neuropeptides are regulated by macronutrients – such as glucose, fat and amino acids – and how such brain macronutrient sensing changes eating behavior (Figure 1).

Researchers have systematically examined the effects of long-term macronutrient restriction on eating behavior and NPY gene expression in the brain. NPY gene expression was elevated in diet-restricted animals as well as in protein-restricted animals, while carbohydrate or fat restriction alone had no effect on NPY gene expression or on food intake. For long-term mechanisms of energy balance, both dietary-fat and carbohydrate energy sources can substitute for one another and signal adequate energy status. For short-term eating behavior, there is evidence that glucose, amino acids and lipids (or fats) are sensed and result in short-term changes. For example, intravenous infusions of glucose, amino acids and lipid emulsions reduce food intake. Blockers of glucose and fatty acid utilization result in short-term stimulation of food intake.

Protein levels
When the protein level in the diet is below the requirement for normal growth or maintenance, animals will overeat or select a higher-protein diet to maintain protein balance. Animals can sense an essential amino acid imbalance in the diet within 15 minutes and will avoid that diet when given an adequate one. LSU AgCenter research on amino acid sensing is focused only on diets that include all essential amino acids. The research has shown evidence for mechanisms of specific nutrient sensing and has led to a hypothesis proposing a final common pathway linked to both the energy status of the cell and stimulation of genes involved in control of eating behavior.

Carbohydrates
Eating behavior is altered by glucose status. There is significant evidence of a connection between carbohydrate, or glucose sensing, and eating behavior. Glucose-sensing mechanisms are highly conserved; some of the proteins involved are similar in yeast and mammals. Specific areas of the brain and gut are activated in this process. An elegant neural network of neurochemical signaling pathways is involved in the modification of eating behavior and glycemic control.

Lipid and fatty acids
Fatty acid sensing occurs in the tongue, small intestine, liver, pancreas and brain. Focusing on macronutrient sensing in the brain, AgCenter research has shown that fatty acid uptake, fatty acid oxidation and fatty acid synthesis in hypothalamic areas are influenced by fat intake and energy status. It also has shown that stimulation of fatty acid oxidation and suppression of fatty acid synthesis result in a decrease in eating behavior.
 
Brain signaling
The enzyme mammalian target of rapamycin (mTOR) is classically associated with cellular nutrient sensing and links nutrient and growth factor signaling to cellular protein metabolism. mTOR signaling is particularly sensitive to amino acids, especially the branched-chain amino acid leucine. AgCenter researchers have demonstrated that amino acids stimulate mTOR signaling in hypothalamic brain cells in vitro (in an artificial environment outside the body) and that this activation of mTOR is necessary for amino acid-dependent regulation of AGRP gene expression. These data collectively establish a mechanism that couples amino acid signaling, eating behavior and neuropeptide gene expression.

The enzyme AMP-activated protein kinase (AMPK) is another cellular energy sensor that contributes to the hypothalamic regulation of food intake. AMPK is activated in settings of cellular energy depletion and acts to enhance processes that increase ATP generation and inhibit those which consume ATP. AgCenter research on the important role of AMPK in the regulation of food intake provides strong evidence that glucose regulates food intake through the interaction with AMPK pathways. Both AMPK and mTOR enzymes are potential targets for bioactive foods.

In the future
Future studies will apply this basic knowledge to identify bioactive food components that exert their effects directly on the brain or indirectly through signaling through the gastrointestinal tract. The ability to modify the most powerful brain signals that control feeding behavior will provide economic opportunities for new food crops and enhance the health of Louisiana citizens.

Roy J. Martin, Professor, Director and Gordon D. Cain Endowed Chair, and Michael J. Keenan, Associate Professor, School of Human Ecology; Christopher Morrison, Assistant Professor, Pennington Biomedical Research Center, Baton Rouge, La.; and Jun Zhou, Instructor, School of Human Ecology, LSU AgCenter, Baton Rouge, La

(This article was published in the fall 2008 issue of Louisiana Agriculture.)

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