The leptin hypothesis of depression: a potential link between mood disorders and obesity?
Introduction
Depression is the most prevalent and life-threatening mental disorder with an overall lifetime prevalence rate of ∼20% of the population worldwide. Current treatment of depression is dominated by antidepressants that exert their therapeutic effects via promoting monoaminergic neurotransmission [1, 2]. However, the monoamine-based antidepressants do not fulfill our expectations in terms of efficacy, onset of action, and tolerability. A substantial proportion of depressed patients shows no response to current available antidepressants, and only less than half of drug-responsive patients achieve full remission. In addition, the slow onset of therapeutic action and side-effects press the need for new antidepressants with novel mechanisms of action. Recent research suggests that leptin, secreted by adipocytes, may be a novel antidepressant. In this review, recent findings on the potential role of leptin in depression and possible mechanisms by which leptin functions as an antidepressant will be discussed.
Section snippets
Leptin and its receptors
Leptin is a peptide hormone, encoded by the obese (ob) gene. Once secreted from adipocytes, leptin circulates in the blood as a 16-kDa protein and enters the brain by a saturable transport mechanism. Leptin was initially identified as an anti-obesity hormone, acting as a negative feedback adiposity signal to control energy homeostasis by interacting with its receptors in the hypothalamus [3]. The leptin receptor is a single membrane-spanning protein that belongs to the class I cytokine receptor
Animal studies
Chronic stress acts as a predisposing and participating factor in the onset of depression in humans. Rats or mice exposed to chronic unpredictable stress or chronic social defeat stress develop behavioral deficits and endocrine abnormalities, mimicking the symptoms of human depression. While acute stress had no effect on levels of leptin, rats exposed to chronic unpredictable stress or chronic social defeat stress showed decreased basal levels of leptin in plasma [7]. This decrease in
Interaction of leptin with monoamines
Reduced monoaminergic transmission has been implicated in the pathogenesis of depressive disorders, and current antidepressants exert therapeutic actions by promoting monoaminergic neurotransmission via interaction with receptors, transporters and/or metabolism. One important question that needs to be addressed is whether leptin modulates monoamine neurotransmission. A high percentage of 5-HT neurons in the raphe nuclei and dopamine neurons in the ventral tegmental area (VTA) expresses the
Impact of leptin on HPA
Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis is a common feature of some patients with major depression. The HPA axis abnormality is characterized by the overproduction of corticotrophin-releasing hormone (CRH), elevated cortisol levels, exaggerated cortisol response to adrenocorticotropic hormone (ACTH), dexamethasone-mediated negative feedback resistance, and enlargement of the pituitary and adrenal glands [8]. The malfunction of the HPA axis can be corrected by
Neurotrophic actions of leptin
Loss of neurotrophic support has been hypothesized to underlie depressive disorders. Patients with depression show atrophy of certain limbic structures, including the hippocampus and prefrontal cortex [54]. Conversely, antidepressant treatment can reverse neuronal atrophy and cell loss and stimulate neurogenesis [54]. Several lines of evidence suggest that leptin has neurotrophic effects. First, leptin deficiency in ob/ob mice leads to reduced brain weight and cortical volume and decreased
Conclusions and perspectives
Since its discovery more than a decade ago, leptin has been well recognized as an adiposity negative feedback signal and a crucial mediator of energy homeostasis. This review discusses an emerging, novel function of leptin: its role in depression. The data favor the hypothesis that leptin insufficiency and/or leptin resistance may contribute to the vulnerability to depression and that leptin and leptin receptor signaling may serve as potential targets for antidepressant drugs. The leptin
Acknowledgements
Preparation of this review and our research cited in this article were supported by grants from the National Institute of Mental Health (NIMH073844 and NIMH076929) and American Heart Association (AHA0530345N). The author would like to thank Alan Frazer and Bai Lu for their comments on the manuscript.
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