Do leptin and insulin signal adiposity?

The physiological regulation of adiposity is supposed to depend on endocrine 'adiposity signals' that inform the brain about the mass of the adipose tissue. Basal levels of insulin and leptin are widely accepted to be adiposity signals, and amylin, ghrelin and peptide YY have been hypothesized to be. Support for these ideas comes from associations between basal hormone levels and levels of adiposity, from demonstrations of receptors for these hormones in neural circuits supposed to regulate energy homeostasis, from neuropharmacological manipulations of the hormones' actions on eating and energy expenditure, and from the effects on energy balance in animals or people bearing mutations in these endocrine signaling pathways. This chapter focuses on only the first of these four types of evidence and only on insulin and leptin. We ask whether circulating levels of either hormone indeed encodes the necessary information to act as an adiposity signal. In considering this question, we emphasize the distinction between regulation of AT mass in steady versus dynamic states. We argue that the best experimental designs for identifying potentially effective adiposity signals involve situations in which the level of adiposity is changing as the organism responds to imposed perturbations. Traditionally, this is the type of design that most convincingly supports the idea that adiposity is actively regulated. Unfortunately, there are few of such studies for any of the hypothesized endocrine adiposity signals, and the evidence that is available does not strongly support the hypotheses. Therefore, we conclude that the question of how adiposity is signaled to the brain remains an open frontier in the physiology of energy homeostasis.