Table 2.

Criteria to assess physiological status of GI hormones in meal-related functions

1. Concentrations of the hormone change at the site of action in a pattern consistent with the effect.*

2. Cognate receptors for the hormone are expressed at its site(s) of action.

3. Exogenous administration of the hormone in amounts duplicating the meal-related changes in endogenous patterns at the site of action produces the effect.

4. Administration of secretagogues for the hormone produce effects similar to the effect of the hormone.

5. The hormone's effect occurs in the absence of abnormal behavioral, physiological, or subjective effects.

6. Administration of selective agonists and antagonists of the hormone's receptors produce effects that are consistent with their receptor pharmacologies.†‡

^*These criteria extend earlier versions (265, 268, 696) to accommodate paracrine and neuropod signaling as well as endocrine signaling, as described in the text.

^†At a minimum, the change in concentrations of the proposed signal should precede the effect; see Geary (265) for discussion. For example, administration of specific and potent receptor antagonists should delay or reduce eating in the case of a hunger signal or increase eating in the case of a satiation signal.

^‡We do not include phenotypic evaluation of global transgenic or spontaneous genetic loss-of-function models in this criterion. These are valuable research tools, but complications due to developmental compensatory effects, pleiotropic actions, and species differences preclude their use as a “necessity” criterion for physiological function. Rapidly inducible, tissue-specific reductions in gene function, however, may complement the use of receptor antagonists in establishing necessity.