Extrahypothalamic effects of leptin: a therapeutic for depression and dementia?

The discovery of leptin ended a mystery of 40 years. In 1950, Ingalls et al. (1) reported mutant mice notable for their extreme obesity. Parabiosis experiments some 20 yr (2) later showed that a fat-reducing substance was missing from the blood of these mice. Finally, in 1994, Jeff Friedman and co-workers (3) determined that this missing substance was a protein secreted from fat, which they named “leptin.” For a brief time, it seemed that leptin was the adipostat: the hormone that puts the brakes on feeding, the accumulation of adipose tissue, and the development of obesity. But central and peripheral tissues become resistant to the anorectic effects of leptin in obesity, and so new mysteries soon arose. Why do humans almost exclusively develop “leptin resistant” forms of obesity, why does leptin have so many actions other than those related to feeding (including on neurogenesis and memory), what are leptin receptors doing in so many locations outside the hypothalamic feeding centers (from hippocampus to macrophages), why (given that the sole absence of leptin produces such profound obesity) are there so many other endogenous substances secreted from peripheral and brain tissues that also affect feeding? Leptin has been a “breach birth” discovery: presented with the one aspect of its spectrum of activities, we labor to discover its true nature. The article by Yamada et al. (4) challenges some conventional views of leptin. Yamada et al. present evidence that an absence of leptin action in the hippocampus is associated with depressive behavior in mice as assessed by the forced swimming test. This article joins a relatively small literature that has shown extrahypothalmic, nonanorectic actions for leptin. Conceptually, this and the related literature are a direct extension of investigations into the pluripotent, extrahypothalamic nature of peptide and protein hormones begun in the 1970s by Kastin et al. (5). Leptin acting in the hippocampus suggests that still other brain regions may mediate other actions of leptin. This challenges the nuclear view of an arcuate eminent in all actions of leptin. The question of whether leptin resistance extends to nonanorectic actions is raised in this article as well. Yamada et al. found that leptin was ineffectual in improving performance of forced swimming test in mice made obese by a high-fat diet. This is the type of model in which resistance to leptin’s anorectic effects occur. This dual resistance is not altogether surprising, because leptin would have to cross the blood-brain barrier to reach either the hypothalamic or the hippocampal receptors. Because the blood-brain barrier is a site of resistance early in obesity, it is likely that all actions of leptin mediated through the central nervous system (CNS) will show resistance in obesity. That resistance also occurs at leptin receptors is strikingly shown in peripheral tissues that have been isolated from obese animals. These peripheral tissues do not fully respond to leptin even when tested in vitro away from immediate metabolic influences and without a requirement for blood-brain barrier transport (6, 7). Leptin’s possession of antidepressant activity resonates with studies in humans showing links among depression, adiposity, and proinflammatory states. Sequential equation modeling elucidates a pathway in which depressioninduced obesity results in increased secretion of IL-6 both