My first clue that leptin might be a regulator of glutamate metabolism came from this study;
Protein appetite is increased after central leptin-induced fat
Leptin reduces body fat selectively, sparing body protein. Accordingly, during chronic leptin administration, food intake is suppressed, and body weight is reduced until body fat is depleted. Body weight then stabilizes at this fat-depleted nadir, while food intake returns to normal caloric levels, presumably in defense of energy and nutritional homeostasis. This model of leptin treatment offers the opportunity to examine controls of food intake that are independent of leptin's actions, and provides a window for examining the nature of feeding controls in a "fatless" animal. Here we evaluate macronutrient selection during this fat-depleted phase of leptin treatment. Adult, male Sprague-Dawley rats were maintained on standard pelleted rodent chow and given daily lateral ventricular injections of leptin or vehicle solution until body weight reached the nadir point and food intake returned to normal levels. Injections were then continued for 8 days, during which rats self-selected their daily diet from separate sources of carbohydrate, protein, and fat. Macronutrient choice differed profoundly in leptin and control rats. Leptin rats exhibited a dramatic increase in protein intake, whereas controls exhibited a strong carbohydrate preference. Fat intake did not differ between groups at any time during the 8-day test.
Leptin seems to decrease appetite in rats only until fat mass is depleted. After that, appetite returns, and is similar in calories to non-leptin treated animals, but food preference changes to protein from carbohydrate in comparison to control rats. This suggests that rather than regulating calories, it regulates appetite for protein. In a similar way, insulin infusions will increase the appetite for glucose.
Now, glucose tastes sweet, so I wondered if there was a particular taste associated with leptin. I was looking for a protein taste, so umami seemed like a likely possibility. And umami is specific to glutamate.
So I needed a study showing the secretion of leptin in reaction to proteins. And I found it in this;
Regulation of leptin secretion from white adipocytes by insulin, glycolytic
substrates, and amino acids
The aim of the present study was to determine the respective roles of energy substrates and insulin on leptin secretion from white adipocytes. Cells secreted leptin in the absence of glucose or other substrates, and addition of glucose (5 mM) increased this secretion. Insulin doubled leptin secretion in the presence of glucose (5 mM), but not in its absence. High concentrations of glucose (up to 25 mM) did not significantly enhance leptin secretion over that elicited by 5 mM glucose. Similar results were obtained when glucose was replaced by pyruvate or fructose (both 5 mM). L-Glycine or L-alanine mimicked the effect of glucose on basal leptin secretion but completely prevented stimulation by insulin. On the other hand, insulin stimulated leptin secretion when glucose was replaced by L-aspartate, L-valine, L-methionine, or L-phenylalanine, but not by L-leucine (all 5 mM). Interestingly, these five amino acids potently increased basal and insulin-stimulated leptin secretion in
the presence of glucose.
Unexpectedly, L-glutamate acutely stimulated leptin secretion in the absence of glucose or insulin.
Finally, nonmetabolizable analogs of glucose or amino acids were without effects on leptin secretion. These results suggest that 1) energy substrates are necessary to maintain basal leptin secretion constant, 2) high availability of glycolysis substrates is not sufficient to enhance leptin secretion but is necessary for its stimulation by insulin, 3) amino acid precursors of tricarboxylic acid cycle intermediates potently stimulate basal leptin secretion per se, with insulin having an additive effect, and 4) substrates need to be metabolized to increase leptin secretion.
Various proteins stimulate leptin secretion in the presence of insulin or glucose. But only glutamate was found to stimulate leptin in their absence. This makes glutamate an excellent candidate for the protein regulated by leptin. The effect of other proteins on leptin secretion is likely an artifact of their interaction with glutamate.
Glutamate metabolites feed into the krebs cycle at several points. Fat cannot be metabolized for energy without this cycle, which explains the apparent control by leptin of appetite which disappears once fat is depleted. This is clearly true.
Poorly-regulated glutamate causes excitotoxicity in the brain, killing neurons. This is a protein needing careful regulation. The possibility that some disregulation of leptin/glutamate metabolism is involved in some neuro-degenerative disorders seems obvious.
Various proteins stimulate leptin secretion in the presence of insulin or glucose. But only glutamate was found to stimulate leptin in their absence. This makes glutamate an excellent candidate for the protein regulated by leptin. The effect of other proteins on leptin secretion is likely an artifact of their interaction with glutamate.Glutamate metabolites feed into the krebs cycle at several points. Fat cannot be metabolized for energy without this cycle, which explains the apparent control by leptin of appetite which disappears once fat is depleted. This is clearly true. Poorly-regulated glutamate causes excitotoxicity in the brain, killing neurons. This is a protein needing careful regulation. The possibility that some disregulation of leptin/glutamate metabolism is involved in some neuro-degenerative disorders seems obvious.
Notice that fat consumption was no different in the leptin-treated rats than in the control mice in that first study. This is because leptin does not directly regulate fat.
Also notice that although the two sets of rats were in drastically divergent hormonal states, they still took in the same number of calories. My guess would be that this has more to do with the amount of work being done in the body than anything else. Matt Stone may have a point; if the body expresses hunger, something, somewhere needs doing. I would disagree with him that calories matter in this; appetite, and the senses, should be trusted. We've forgotten how to trust all of our senses. That's why nobody seems to notice anymore when they make a major nutritional scientific breakthrough.
We really need to live in the real world.