Role of Leptin in Depression and Obesity

Question:

“You mentioned that leptin may have a potential role in the treatment of depression at a Treating the Whole Patient  lecture presented at the  2010 Psych Congress . I’ve never heard of that; could you elaborate on the notion that there is a link between leptin, mood disorders, and obesity?”

Jon W. Draud, MD, MS:   This is an excellent question and since its discovery approximately 10 years ago, leptin has been noted to be a critical mediator of energy homeostasis and serve as an adiposity negative feedback signal. There is also a putative role for leptin in the treatment of depression.

We know that depression is the most life-altering and prevalent of all mental disorders with a prevalence rate of about 20% worldwide. Current treatments for depression are all focused on compounds that exert therapeutic effects via promoting monoaminergic neurotransmission, but we know that these compounds often do not allow us to bring patients to a state of remission. ^1,2

Leptin is a peptide hormone secreted from adipocytes initially identified as an anti-obesity hormone. Newer evidence expands the potential role from energy homeostasis to regulation of reproduction and cognition. ^3,4  Support for this expanded role is that leptin receptors are found in numerous brain regions including cortex, amygdala, and hippocampus—areas known to control emotion and mood.

In animal studies, rats exposed to chronic, but not acute stress showed decreased levels of plasma leptin. ⁵  Based on this, it was hypothesized that leptin insufficiency may contribute to depression-like behaviors, ie, reduction of sucrose preference, which is seen as anhedonia in animal studies of depression. ^6,7  Studies have shown that systemic administration of leptin can reverse this stress-induced reduction for sucrose preference. ⁵ Despair is another depressive symptom that can be measured by the forced Swim test and tail suspension test in studies, and on both of these measures the systemic administration of leptin was shown to produce a dose-dependent reduction of immobility, ie, reduction of depressive symptoms. ^5,8

Human studies regarding leptin are limited, but there seems to be a loose association between reduced leptin levels and depression. ^9-12  Interestingly, there is a 20% more likely incidence of depression in obese patients and they actually have high leptin levels, but it is due to leptin resistance much like insulin resistance in diabetes. Therefore, leptin resistance seems to be the link to greater depression in obese patients.

Briefly we will discuss the role of leptin as it relates to monoamines, HPA, and neurotrophins. Some studies show that serotonin content and metabolism are increased by leptin in forebrain, ^13,14  and others show that leptin enhances mesolimlic dopamine activity. ¹⁵  Accumulating evidence shows that leptin modulates HPA activity, which is implicated in depression. Chronic administration of leptin can reverse hypercortisolemia even prior to weight loss in mice, ^16,17  and there is an inverse relationship between plasma leptin glucocorticoids and circadian rhythm activity. ¹⁸

Finally, several studies link leptin to the neurotropic hypothesis of depression, and leptin actually has neurotropic effects itself. First, leptin deficiency leads to reduced brain volume in mice, ^19,20  and leptin treatment causes protein synthesis and synaptic connectivity in rats. ²¹  Leptin has also been shown to be critical for certain pathway formations at hippocampus. ^22,23

In conclusion, there seems to be emerging evidence that leptin does have a role in possibly the etiology and future treatment of depressive disorders. The leptin hypothesis is complimentary to the other major prevailing hypotheses in depression (monoamine HPA, and neurotrophic) and will be interesting to follow as clinicians.

—Jon W. Draud, MD, MS

References

1. Berton O, Nestler EJ.  New approaches to antidepressant drug discovery: beyond monaamines.  Nat Rev Neurosci.  2006;7(2):137-151.
2. Frazer A.  Pharmacology of antidepressants.  J Clin Psychopharmacol.  1997;17(suppl 1):2S-18S.
3. Chehab FF.  Leptin as a regulator of adipose mass and reproduction.  Trends Pharmacol Sci.  2000;21(8):309-314.
4. Farr SA, Banks WA, Morley JE.  Effects of leptin on memory processing.  Peptides. 2006;27(6):1420-1425.
5. Lu XY, Kim CS, Frazer A. Zhang W.  Leptin: a potential novel antidepressant.  Proc Natl Acad Sci U S A.  2006;103(5):1593-1598.
6. Katz RJ.  Animal model of depression: pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav.  1982;16(6):965-968.
7. Willner P.  Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological condcordance in the effects of CMS.  Neuropsychobiology.  2005;52(2):90-110.
8. Kim CS, Huang TY, Garza J, et al. Leptin induces antidepressant-like behavioral effects and activates specific signal transduction pathways in the hippocampus and amygdala of mice.  Neuropsychopharmacology.  2006;31(suppl 1S):S237-S238.
9. Jow GM, Yang TT, Chen CL.  Leptin and cholesterol levels are low in major depressive disorder, but high in schizophrenia.  J Affect Disord.  2006;90(1):21-27.
10. Kraus T, Haack M, Schuld A, Hinze-Selch D, Pollmacher T.  Low leptin levels but normal body mass indices in patients with depression or schizophrenia. Neuroendocrinology.  2001;73(4):243-247.
11. Atmaca M, Kulogla M, Tezcan E, et al.  Serum leptin and cholesterol values in suicide attempters.  Neuropsychobiology.  2002;45(3):124-127.
12. Westling S, Ahren B, Traskman-Bendz L, Westrin A.  Low CSF leptin in female suicide attempters with major depression.  J Affect Disord.  2004;81(1):41-48.
13. Calapai G, Corica F, Corsonello A, et al.  Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis.  J Clin Invest.  1999;104(7):975-982.
14. Hastings JA, Wiesner G, Lambert G, et al.  Influence of leptin on neurotransmitter overflow from the rat brain in vitro.  Regul Pept.  2002;103(2-3):67-74.
15. Fulton S, Pissios P, Manchon RP, et al.  Leptin regulation of the mesoaccumbens dopamine pathway.  Neuron.  2006;51(6):811-822.
16. Chen H, Carlat O, Tartaglia LA, et al.  Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell.  1996;84(3):491-495.
17. Chua SC Jr, Chung WK, Wu-Peng XS, et al.  Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor.  Science.  1996;271(5251):994-996.
18. Stephens TW, Basinski M, Bristow PK, et al.  The role of neuropeptide Y in the antiobesity action of the obese gene product.  Nature.  1995;377(6549):530-532.
19. Licinio J, Mantzoros C, Negrao AB, et al.  Human leptin levels are pulsatile and inversely related to pituitary-adrenal function.  Nat Med.  1997;3(5):575-579.
20. Ahima RS, Bjorbaek C, Osei S, Flier JS.  Regulation of neuronal and glial proteins by leptin: implications for brain development.  Endocrinology.  1999;140(6):2755-2762.
21. Steppan CM, Swick AG.  A role for leptin in brain development.  Biochem Biophys Res Commun.  1999;256(3):600-602.
22. Proulx K, Clavel S, Nault G, Richard D, Walker CD.  High neonatal leptin exposure enhances brain GR expression and feedback efficacy on the adrenocortical axis of developing rats.  Endocrinology.  2001;142(11):4607-4616.
23. Bouret SG, Draper SJ, Simerly RB.  Trophic action of leptin on hypothalamic neurons that regulate feeding.  Science.  2004;304(5667):108-110.