Date: May 19, 2008

Speaker's Name, Affiliation:

Michael Tordoff
Calcium Appetite

Seminar Title: "Calcium Appetite"

Presiding Chair: Harry R. Kissileff, Ph.D.

Rapporteur: Kathleen L. Keller, Ph.D.

Attendees and their Affiliation:

Kathleen Keller	Columbia/Obesity Research Center
Harry Kissileff	Obesity Research Center
Rich Bodnar	Queens College
Chris Ochner	NYORC
Susan Carnell	NYORC
Rhoda Gruen	Columbia University
Joel Grinker	University of Michigan
Julie Pearson	Columbia Mailman

Summary: (Prepared by the Rapporteur)

Calcium is a nutrient that plays an integral role in bone health and many other biological processes, but most Americans do not consume the recommended daily requirements. Dr. Michael Tordoff's lab at the Monell Chemical Senses Center has been using genes to determine whether humans have a "calcium appetite" and to find out if this appetite is influenced by the body's calcium status. However, the study of calcium appetite has largely been ignored by the field of ingestive behavior, a fact that Dr. Tordoff suggests is in part due to the difficulty in making the connection between calcium and disease states (in comparison to the obvious connections between other relationships, such as consumption of energy dense foods and obesity). Indeed, there are many serious conditions that can result from consuming too little calcium in the diet. For example, osteoporosis, hypertension, and obesity are three diseases that are associated with consuming a low calcium diet.

Because calcium is a required nutrient, it would make sense to consider that humans might have an "appetite" for this nutrient, or at the very least, some oral mechanism of sensing it. Evidence to support this notion comes from both animals in humans. Tordoff (1994) found that rats will spontaneously consume solutions of calcium chloride(CaCl2) to a greater extent than water until concentrations of CaCl2 go above about 1 mM. This spontaneous consumption is similar to that seen with NaCl solutions. There are other similarities between calcium and salt as well, including evidence that depletion of these nutrients will result in increased sham feeding of both CaCl2 and NaCl. In fact, Tordoff notes that "the evidence is equally strong for calcium and sodium that the appetite is innate and has a dedicated physiological substrate."

What about evidence to support this in humans? There is strong evidence that humans are able to taste calcium, with varying thresholds, and that the taste is a combination of sweet, salty, bitter, and sour (depending on the concentration you are testing). Schiffman SL (1971) developed a psychophysical model for a variety of tastes, and CaCl2 was described as being quite different from any other tastes the subjects had encountered. Recent studies from Tordoff suggest that the taste of calcium at high concentrations may not be altogether pleasant because there is an inverse relationship between calcium concentration in vegetables and their perceived bitterness. Bitter melon, one of the most bitter vegetables (hence the name) also happens to have the highest calcium content. However, there is some evidence that calcium deficiency can influence the perception of calcium: Leshem and colleagues have shown that patients who are hypocalcemic (due to kidney dialysis) prefer cheeses with increased amounts of CaCl2 added. But, this evidence is indirect, and support from a gene responsible for calcium appetite might strengthen the argument.

In order to identify potential genes, Tordoff's lab is currently studying two mice strains that show different phenotypes with respect to calcium preferences: the common B6 strain and the far less common PWK mouse. The PWK mouse has a specific appetite for calcium, while the B6 does not, making them excellent partners for studies to identify candidate genes. One gene of interest is , Casr, the calcium sensing receptor, which shows significant linkages to CaCl2 intake in B6 x PWK F2 mice. Casr is a G-protein coupled receptor, and it's structure is similar to taste receptors for bitter and sweet tastes. It is highly expressed in the kidney, parathyroid gland, gut, and bone, and it is sensitive to extracellular calcium concentrations. This receptor might also be detecting calcium in the mouth, but evidence to support this is still accumulating. Another gene of implicated by a genome screen of B6 x PWK F2 mice is Tas1r3, the so-called "sweet taste receptor". Interestingly, whereas B6 mice avoid high concentrations of calcium, B6 mice with Tas1r3 knocked out are indifferent to them, or even prefer them to water. SNP analyses also suggest that a single nucleotide polymosphism in the Tas1r3 gene determines how much mice like calcium. As speculation, it is possible that Casr may act as a heterodimer with Tas1r3 in determining how much animals like calcium.

Discussion:

Q. Is this calcium carbonate that you use?
A. We use calcium chloride or calcium lactacte

Q. Does it have any taste to it?
A. I'll get to that data in humans in a little bit.

Q. Are there different receptors for sodium and calcium?
A. Well, that's what my research is about and we'll get to that.

Q. Does this threshold (the threshold for calcium in solution) vary by someone's calcium status?
A. Thresholds do vary and my guess is that they do vary with calcium status.

Q. If you ask people to do a simple difference test between sodium and calcium, are they able to tell the difference?
A. Yes. Harry Lawless has done that.

Q. What is bitter melon?
A. It is a vegetable that looks like a cucumber and it is served with a lot of Asian cooking. Take a look at bittermelon.org

Q. Is it definitive that this is actually related to calcium and not some other sensory attribute related to the cheese?
A. The researcher made the cheese himself, so the sensory aspects were somewhat controlled.

Q. Why do you call your experimental approach "hypothesis free."
A. Because we don't identify specific genes that we are looking for before we do the analyses. Maybe "unbiased" is a better term.
Comment: True, but just stating that you believe there is a genetic link is a form of a hypothesis, correct?
A. Yes, I'll give you that.

Q. Because the C57 mice are avoiding calcium, do they have a higher incidence of osteoporosis?
A. I don't know. That's a good question.

Q. Can you taste the difference between OJ with and without calcium added?
A. Some people (and mice) can, but I can't.

Q. I didn't see how you identified the calcium sensor gene.
A. The gene (Casr) was already identified as a calcium sensor. We chose to focus on that one because it seemed like a good candidate, and it turns out, it was a good choice.

Q. Would you get an inverse relationship between bitter and sweet if you looked at preferences for those?
A. No one has looked at that, but I doubt this would be the case.

Q. For your lock and key model, do you have any idea where polycose would fit in?
A. My guess is that Polycose is detected by the sweet taste receptor.