The pre-research years (1956-77)
I was born on a cold, rainy day in Bradford, Yorkshire, lived in several industrial cities in the North East of England as a young child, and spent my formative teenage years as a student at the Royal Grammar School, High Wycombe, which is on the North West edge of the London commuter belt. I studied Psychology as an undergraduate at the University of Leeds.
Doctoral work (1977-83)
Figure 1. The Novin lab at UCLA, circa 1980. From left to right, Peter Cooper, me, Paula Geiselman, Mark Gunion, Donald Novin, and Carlos Grijalva.
From Leeds, I went to the University of California in Los Angeles to complete doctoral work in physiological psychology, with Dr. Donald Novin as my preceptor. While a graduate student, I studied how signals related to hunger and satiety are communicated from the viscera to the brain. My doctoral work involved experiments in which I surgically or chemically destroyed components of the sympathetic nervous system in rats, and measured the resulting changes in feeding behavior. Although the sympathetic nervous system had some acute effects on the anorexia produced by amphetamine (1), and on brown fat metabolism, temperature regulation, and gastric ulceration (2, 3), the most surprising finding was that the rats managed very well without a sympathetic nervous system, showing very little change in behavior (2-5).
Early years at Monell (1983-90)
Given my interests in peripheral signals controlling feeding, it was an easy choice to come to Monell to study with Dr. Mark Friedman, who conceived the most prominent and influential theory to explain how signals generated by metabolism influenced hunger (6). I planned to visit for a year, which soon became two years, and then three, and..., well, I'm still at Monell over 25 years later, having never found a reason to leave.
Liking (and) the Liver. As a postdoc, my initial work was on the role of the liver in feeding. Mark Friedman and I conducted the first parametric studies to determine how glucose entering the liver through the hepatic portal vein influenced food intake and metabolism (7, 8), and we found that these glucose infusions were rewarding (9). This provided a mechanism by which rats -- and presumably people -- too learn to prefer high rather than low-energy density foods (10-12). As part of this work, and with the help of Monell chemists, Bob Rafka and Michael DiNovi, we discovered and patented a fructose analogue, 2,5-anhydro-D-mannitol, which is a sugar that causes rats to eat by influencing liver metabolism (9, 13).
Sweetness and Hunger. Given the emphasis at Monell on taste, it was a small step from sugar to nonnutritive sweeteners. In the late 1980's there was concern that the just-noticed obesity epidemic was coincident with the use of nonnutritive sweeteners, and these concerns were fueled by the controversial introduction of aspartame ("Nutrasweet") into the United States. My interest in this topic began when I discovered that rats given saccharin to drink before a regular meal ate more food than if they were given just water to drink. The animal model allowed tests of potential mechanisms. I found that a combination of cephalic phase reflexes, over-hydration, and learning accounted for the increase in food intake (14-20). These results prompted me to conduct parallel experiments with humans. Consistent with the rat studies, I found that people who chewed aspartame-sweetened gum reported being hungrier than people who chewed unsweetened gum (21). However, these effects were ephemeral and were restricted to a narrow sweetener concentration range. Moreover, in another experiment, young men and women required to drink 40 oz/day of diet cola for 3 wk lost weight slightly, in contrast to a similar period when given regular cola, when they gained weight significantly (22). My interpretation of these findings, and subsequent work by other investigators, is that nonnutritive sweeteners can stimulate appetite but their effects are negligible under real-world conditions. It will be interesting to see how this field progresses given the recent re-kindling of interest due to the discovery of sweet taste receptors in the gut.
Monell at the end of the last century (1990-2000)
Salt and the liver. In contrast to the study of food intake, which was dominated mostly by brain mechanisms, the study of salt (sodium) consumption was historically focused on hormonal mechanisms. A great deal of data supported the idea that the combined action of angiotensin and aldosterone in the brain initiated salt hunger, but there was very little work on what turned off this appetite. What signaled satiety for salt? Driven primarily by the gentle goading and indefatigable optimism of Dr. Jay Schulkin, I used the methods I had already developed to investigate the hepatic control of food intake to examine whether similar controls influenced salt intake. Our work showed that the satiety for salt could be accounted for by hepatic-portal sodium receptors (23, 24). Consideration of the time required for gastric emptying and the physical constraints on absorption also explained why salt-hungry rats drink more sodium than they need (25) but do not eat more sodium in salty food than they need (26).
Dietary calcium and sodium intake. In 1990, I found that rats with free access to NaCl solution drank progressively larger volumes of it when switched to a low-calcium diet. This was an impressive phenomenon, with some rats drinking their body weight in 300 mM NaCl solution every night (27). Moreover, a strain of rats that usually avoided NaCl drank it avidly after a few days of dietary calcium deprivation (28). These findings had obvious implications for humans, who consume less calcium and more sodium than we should (29). I exploited the animal model to characterize the physiology involved (30-32). A conceptual breakthrough came from the finding that drinking NaCl increases blood ionized calcium concentrations (33). I now believe that the basis of this phenomenon is like an addiction. Rats drink sodium because it makes calcium in their blood more available and so they feel less calcium-deficient. Unfortunately, the sodium they ingest must be excreted, and calcium excretion is linked to sodium excretion, so the net result is a loss of calcium. Thus, the rat drinks sodium for short-term relief but hastens the progression of its deficiency. Whether the same mechanism can explain the human fondness for salt remains to be determined, although I have collected some data consistent with it (34).
Calcium appetite - an innate behavior. Given the profound influence of dietary calcium on sodium appetite it was an obvious step to look at calcium appetite. With the help of Susan Coldwell, and later, Stuart McCaughey, we conducted some fundamental studies to investigate the behavior. We found that replete rats drank low (millimolar) concentrations of calcium salts in preference to water (35) and, like humans (36), they avoided high concentrations. However, calcium-deficient rats drank calcium solutions avidly, and smiled while they did so (37). Moreover, they learned to anticipate the beneficial effects of calcium even when calcium replete (38). This was mediated by the taste of calcium: Calcium-deficient rats showed increased intakes of calcium solution within seconds of starting to drink them (39), and drank large volumes even if postingestive signals were eliminated (40). Moreover, calcium deficiency caused changes in the electrophysiological response elicited by calcium in the oral cavity (41, 42).
Figure 1. Model describing the controls of calcium consumption. Blood ionized calcium influences activity of circuitry in the subfornical region (Brain) and also the sensitivity of the tongue to calcium.
Calcium appetite - specificity. The specificity of specific appetites has been an historically enduring issue, and we confronted it while investigating calcium appetite. Calcium-deprived rats that were offered a choice between water and a mineral salt solution would drink more of the solution than would control rats fed a replete diet (39, 43). We suspect this is because most minerals can substitute to some extent for calcium, and thus, as is the case for sodium, calcium-deprived rats ingest them because this provides some relief from deficiency. Understanding why rats have inappropriate intakes is important. For example, calcium deficiency has been blamed for pica and the consumption of lead paint by children. An interesting and still unexplained finding was that calcium-deprived rats avoid sweet compounds (44). It is important to note that these deficiency-induced changes in preference occur only when calcium is absent. Calcium deficient rats ingest calcium in preference to other minerals in choice tests (45).
Calcium appetite - physiological basis. What are the physiological mechanisms underlying calcium appetite? We first investigated the contribution to calcium appetite of the three major calcium-regulatory hormones, parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. In a series of studies involving classic tissue ablation and replacement therapies, we found that each of these hormones influenced calcium intake but their effects could best be explained by their actions on blood calcium levels rather than direct actions on the brain. Work from other labs had shown that the subfornical organ of the brain had a high density of calcium-sensing receptors and was responsive to blood calcium concentration (46). We found that unlike intact rats, rats with lesions of the subfornical organ failed to respond to calcium deficiency by drinking calcium solution (47). We hypothesize that this brain region is responsible for detecting circulating calcium concentrations and activating brain circuitry that causes the rat to seek calcium.
Monell in the new millennium (2000 - 2009)
Figure 2. A PWK/Phj mouse, notable for its strong appetite for calcium.
Calcium appetite - The promise of genetics. In 2001, my colleagues and I used the "gene discovery" or "QTL" approach to positionally clone Tas1r3 (48), which is the gene responsible for a subunit of the mammalian sweet and umami taste receptors. This has led to more than 100 publications to date, many insights, and rapid progress toward understanding sweet taste perception. More importantly from my point of view, it demonstrated that the gene discovery approach could be used to identify physiological mechanisms even when there were no prior hypotheses. It seemed particularly well-suited to study calcium appetite, for which only a little about mechanism was known. Consequently, with the help of Monell staff, Drs. Dani Reed and Sasha Bachmanov, I switched from a physiological to a genetic approach to understand the mechanisms responsible for calcium appetite.
The first step was to find some genetically-mediated variation in calcium consumption. To this end, we tested 40 inbred strains of mice and discovered that, in contrast to the C57BL/6J and most other strains, the PWK/PhJ strain had avid calcium preferences (49). To exploit this, I bred C57BL/6J x PWK/PhJ F2 mice, measured their calcium preferences, and conducted a genome scan (50, 51). This revealed two chromosomal regions that were linked to calcium preference. One linkage was due to the gene we cloned earlier,Tas1r3. This was a serendipitous coincidence because we already had available the reagents to isolate and study it (e.g., knockout mice, antibodies), so identification and characterization was relatively fast (52). The other linkage was accounted for by the calcium-sensing receptor gene, Casr (50, 51), which had not previously been implicated in taste transduction.
Figure 3. Taste buds showing fluorescent antibody for the calcium-sensing receptor, CaSR.
The clues from gene identification led us to search for and identify CaSR in taste receptor cells, find mutations in the PWK/PhJ mouse form of Casr, and demonstrate strain differences in the activity of CaSR that can account for the differences in calcium preferences. This work is ongoing but it strongly implies that there are two gustatory calcium receptors--T1R3 and CaSR--that underlie calcium preference.
Knowing that oral calcium guides the ingestive behavior of mice opens many avenues that are now being explored by my lab and several others. The most important question that remains to be answered is whether oral calcium receptors have any relevance for human calcium consumption.
1. Tordoff MG, Hopfenbeck J, Butcher LL, and Novin DA. A peripheral locus for amphetamine anorexia. Nature 279: 148-150, 1982.
2. Tordoff MG, Grijalva CV, Novin D, Butcher LL, Walsh JH, Pi-Sunyer FX, and VanderWeele DA. Influence of sympathectomy on the lateral hypothalamic lesion syndrome. Behav Neurosci 98: 1039-1059, 1984.
3. Tordoff MG, Glick Z, Butcher LL, and Novin D. Guanethidine sympathectomy does not prevent meal-induced increases in the weight or oxygen consumption of brown fat. Physiol Behav 33: 975-979, 1984.
4. Tordoff MG, VanderWeele DA, Katz TJ, Chene WS, and Novin D. Meal patterns and glucoprivic feeding in the guanethidine-sympathectomized adrenodemedullated rat. Physiol Behav 32: 229-235, 1984.
5. Tordoff MG. Influence of sympathectomy on body weight of rats given chow or supermarket diets. Physiol Behav 35: 455-463, 1985.
6. Friedman MI and Stricker EM. The physiological psychology of hunger: A physiological perspective. Psych Rev 83: 409-431, 1976.
7. Tordoff MG and Friedman MI. Hepatic control of feeding: effect of glucose, fructose and mannitol infusion. Am J Physiol 254: R969-R976, 1988.
8. Tordoff MG, Tluczek JP, and Friedman MI. Effect of hepatic portal glucose concentration on food intake and metabolism. Am J Physiol 257 (Regulatory Integrative Comp. Physiol. 26): R1474-R1480, 1989.
9. Tordoff MG, Rafka R, DiNovi MJ, and Friedman MI. 2,5-Anhydro-D-mannitol: a fructose analogue that increases food intake in rats. Am J Physiol 254: R150-R153, 1988.
10. Tordoff MG. Metabolic basis of learned food preferences. In: Chemical senses: appetite and nutrition, edited by Friedman MI, Kare MR and Tordoff MG. New York: Marcel Dekker, 1991, p. 239-260.
11. Tordoff MG, Tepper BJ, and Friedman MI. Food flavor preferences produced by drinking glucose and oil in normal and diabetic rats: Evidence for conditioning based on fuel oxidation. Physiol Behav 41: 481-487, 1987.
12. Tordoff MG, Ulrich PM, and Sandler F. Flavor preferences and fructose: evidence that the liver detects the unconditioned stimulus for calorie-based learning. Appetite 14: 29-44, 1990.
13. Tordoff MG, Rawson N, and Friedman MI. 2,5-Anhydro-D-mannitol acts in liver to initiate feeding. Am J Physiol 261: R283-R288, 1991.
14. Tordoff MG. Sweeteners and appetite. In: Sweeteners: Health effects, edited by Williams GM. Princeton, NJ: Princeton Scientific, 1988, p. 53-60.
15. Tordoff MG. How do nonnutritive sweeteners increase food intake? Appetite 11: 5-11, 1988.
16. Tordoff MG. Saccharin and food intake. In: Low-calorie products, edited by Birch GG and Lindley MG. London: Elsevier Applied Science, 1988, p. 127-146.
17. Tordoff MG and Friedman MI. Drinking saccharin increases food intake and preference: I. Comparison with other drinks. Appetite 12: 1-10, 1989.
18. Tordoff MG and Friedman MI. Drinking saccharin increases food intake and preference: II. Hydrational factors. Appetite 12: 11-21, 1989.
19. Tordoff MG and Friedman MI. Drinking saccharin increases food intake and preference: III. Sensory and associative factors. Appetite 12: 23-35, 1989.
20. Tordoff MG and Friedman MI. Drinking saccharin increases food intake and preference: IV. Cephalic phase and metabolic factors. Appetite 12: 37-56, 1989.
21. Tordoff MG and Alleva AM. Oral stimulation with aspartame increases hunger. Physiol Behav 47: 555-559, 1990.
22. Tordoff MG and Alleva AM. Effect of drinking soda sweetened with aspartame or high-fructose corn syrup on food intake and body weight. Am J Clin Nutr 51: 963-969, 1990.
23. Tordoff MG, Schulkin J, and Friedman MI. Hepatic contribution to satiation of salt appetite in rats. Am J Physiol 251: R1095-R1102, 1986.
24. Tordoff MG, Schulkin J, and Friedman MI. Further evidence for hepatic control of salt intake in the rat. Am J Physiol 253: R444-R449, 1987.
25. Tordoff MG, Fluharty SJ, and Schulkin J. Physiological consequences of NaCl ingestion by Na+-depleted rats. Am J Physiol 261: R289-R295, 1991.
26. Bertino M and Tordoff MG. Sodium depletion increases rats' preferences for salted food. Behav Neurosci 102: 565-573, 1988.
27. Tordoff MG, Ulrich PM, and Schulkin J. Calcium deprivation increases salt intake. Am J Physiol 259: R411-R419, 1990.
28. Tordoff MG. Calcium deprivation increases NaCl intake of Fischer-344 rats. Physiol Behav 49: 113-115, 1991.
29. Tordoff MG. The importance of calcium in the control of salt intake. Neurosci Biobeh Rev 20: 89-99, 1996.
30. Tordoff MG, Hughes RL, and Pilchak DM. Independence of salt intake from the hormones regulating calcium homeostasis. Am J Physiol 264: R500-R512, 1993.
31. Tordoff MG, Pilchak DM, and Hughes RL. Independence of salt intake induced by calcium deprivation from the renin-angiotensin-aldosterone system. Am J Physiol 264: R492-R499, 1993.
32. Tordoff MG and Okiyama A. Daily rhythm of NaCl intake in rats fed low-Ca2+ diet: relation to plasma and urinary minerals and hormones. Am J Physiol 270: R505-R517, 1996.
33. Tordoff MG. NaCl ingestion ameliorates plasma indexes of calcium deficiency. Am J Physiol 273: R423-R432, 1997.
34. Tordoff MG. Adrenalectomy decreases NaCl intake of rats fed low-calcium diets. Am J Physiol 270: R11-R21, 1996.
35. Tordoff MG. Voluntary intake of calcium and other minerals by rats. Am J Physiol Regulatory Integrative Comp Physiol 267: R470-R475, 1994.
36. Tordoff MG. Some basic psychophysics of calcium salt solutions. Chem Senses 21: 417-424, 1996.
37. McCaughey SA, Forestell CA, and Tordoff MG. Calcium deprivation increases the palatability of calcium solution in rats. Physiol Behav 84: 335-342, 2005.
38. Coldwell SE and Tordoff MG. Latent learning about calcium and sodium. Am J Physiol 265: R1480-R1484, 1993.
39. Coldwell SE and Tordoff MG. Immediate acceptance of minerals and HCl by calcium-deprived rats: brief exposure tests. Am J Physiol 271: R11-R17, 1996.
40. McCaughey SA and Tordoff MG. Calcium-deprived rats sham-drink CaCl2 and NaCl. Appetite 34: 305-311, 2000.
41. Inoue M and Tordoff MG. Calcium deficiency alters chorda tympani nerve responses to oral calcium chloride. Physiol Behav 63: 297-303, 1998.
42. McCaughey SA and Tordoff MG. Calcium deprivation alters gustatory-evoked activity in the rat nucleus of the solitary tract. Am J Physiol Regulatory Integrative Comp Physiol 281: R971-R978, 2001.
43. Coldwell SE and Tordoff MG. Acceptance of minerals and other compounds by calcium-deprived rats: 24-h tests. Am J Physiol 271: R1-R10, 1996.
44. Tordoff MG and Rabusa SH. Calcium-deprived rats avoid sweet compounds. J Nutr 128: 1232-1238, 1998.
45. McCaughey SA and Tordoff MG. Magnesium appetite in the rat. Appetite 38: 29-38, 2002.
46. Tordoff M, Hughes R, and Pilchak D. Calcium intake by the rat: Influence of parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D. Am J Physiol 274: R214-R231, 1998.
47. McCaughey SA, Fitts DA, and Tordoff MG. Lesions of the subfornical organ decrease the calcium appetite of calcium-deprived rats. Physiol Behav 79: 605-612, 2003.
48. Bachmanov AA, Li X, Reed DR, Ohmen JD, Li S, Chen Z, Tordoff MG, de Jong PJ, Wu C, West DB, Chatterjee A, Ross DA, and Beauchamp GK. Positional cloning of the mouse saccharin preference (Sac) locus. Chem Senses 26: 925-933, 2001.
49. Tordoff MG, Bachmanov AA, and Reed DR. Forty mouse strain survey of voluntary calcium intake, blood calcium, and bone mineral content. Physiol Behav 91: 632-643, 2007.
50. Tordoff MG, Reed DR, and Shao H. Calcium taste preferences: Genetic analysis and genome screen of C57BL/6J x PWK/PhJ hybrid mice. Genes Brain Behav 7: 618-628, 2008.
51. Tordoff MG. Gene discovery and the genetic basis of calcium appetite. Physiol Behav 94: 649-659, 2008.
52. Tordoff MG, Shao H, Alarcon LK, Margolskee RF, Mosinger B, Bachmanov AA, Reed DR, and McCaughey SA. Involvement of T1R3 in calcium-magnesium taste. Physiol Genomics 34: 338-348, 2008.