The darkside of leptin

Disclaimer: This post is not related specifically to ketogenic diets or ketosis. 

It is common to see leptin as the "fat-burning" hormone which has antagonizing effects on insulin, the "fat-promoting" hormone. So, in general terms, people tend to see leptin as "good" and insulin as "bad". As I mentioned in my last post, there is no such thing as a bad or good hormone, its all about a correct balance and tissue sensitivity. Before going on discussing leptin, we must review some basics of this molecule. 

Leptin is a 16kDa protein encoded by the ob gene which is produced primarily by adipose tissue so its circulating levels are correlated with adipose tissue mass. Based on its structure and that of its receptor, leptin is a cytokine. It shares many similarities with members of the long chain helical cytokines such as IL-6, IL-1, IL-12, leukemia inhibitory factor (LIF), granulocyte-colony stimulating factor (G-CSF), ciliary neurotrophic factor (CNTF) and oncostatin M (OSM) (1). 

The leptin receptor (OB-R) is related to type I cytokine receptors and form homodimers, both in the absence or presence of ligand. Each receptor binds to one molecule of leptin forming a tetrameric complex composed of two receptors with two leptin molecules. There are different alternatively spliced isoforms of OB-R: OB-Rb mediates leptin's effect in the hypothalamus (weight-regulating effects) but it is also present in several peripheral tissues like endothelial cells, platelets, CD4+ and CD8+ T lymphocytes, CD34+ cells, the yolk sac, the fetal liver, as well as leukemia cells. A short isoform of OB-R is OB-Ra which is found in most tissues and cells like kidney, lung, liver, spleen and macrophages. Other isoform of OB-R is the soluble receptor OB-Re, which bounds leptin in the peripheral circulation. 

We are going to focus in OB-Rb mediated pathway. OB-Rb contains a 302 amino acid cytosolic domain that includes binding motifs associated with the activation of the JAK/STAT signaling pathways. After binding to the receptor, leptin activates STAT-1, -3 and -5. Leptin-OB-Rb interaction has shown to activate the MAPK pathway and induce the expression of supressor of cytokine signaling 3 (SOCS-3), which acts as a negative regulator of its signalling. Leptin increases specifically p38 MAPK phosphorylation and activates the JNK pathway. The main downstream target seems to be NF-kB (2).

Besides its effects in the hypothalamus, leptin, as a pleiotropic protein, has important roles in both immunity and inflammation (reviewed in 3). I will try to summarize what it is known about this relationship.

Leptin and the immune system

Leptin has been shown to promote phagocytosis and induce eicosanoid synthesis, as well as NO and pro-inflammatory cytokines in macrophages and monocytes; increase IFN-gamma induced expression of NO synthase in murine macrophages; induce chemotaxis and the release of ROS in neutrophils and influence proliferation, differentiation, activation and cytotoxicity on natural killer cells (NK). In dendritic cells (DC), leptin upregulates the production of IL-1beta, IL-6, IL-12, TNF-alpha and MIP-1alpha; downregulates IL-10 production and polarizes naive T cells towards Th1 phenotype (4). Moreover, leptin also protects DC from UVB and H2O2-induced apoptosis via NF-kB, bcl-2, bcl-XL and Akt activation (5). 

As studies with db/db mice have shown, leptin is an integral part of the immune system (6). But as a pro-inflammatory cytokine, it has potential downsides.

Leptin and inflammation

Leptin levels have been shown to be elevated during infection and inflammation (7). Exposure to LPS, TNF-a and IL-1 increase its circulating levels and expression in adipose tissue (8). Additionally, leptin increases LPS-stimulated production of TNF-a, IL-6 and IL-12 in murine peritoneal macrophages and human monocytes, as well as TNF-a, IL-1beta and IL-6 from human placenta and adipose tissue (9). This shows a positive feedback between leptin and other pro-inflammatory cytokines. 

Hyperleptinemia has been correlated with cardiovascular disease (10), endothelial dysfunction (11), atherosclerosis (12), arterial hypertension (13), psoriasis (14), multiple sclerosis (15), diabetes (16) and metabolic syndrome (17).

Leptin and cancer

Several in vitro studies have linked leptin signaling to carcinogenesis. For example, leptin and OBR seem to be overexpressed in mammary cancer tissue relative to non-cancer epithelium (18). Leptin has shown to induce growth of breast cancer cells through activation of the JAK/STAT3, ERK1/2 and PI3K pathways, and can mediate angiogenesis by inducing the expression of VEGF (19). Colon cancer cell lines and human colonic tissue also express the OB receptor, and stimulation with leptin induces phosphorylation of p42/44 MAPK and increases proliferation in vitro and in vivo (20). Leptin also induces invasion of colonic cells and formation of lamellipodial structures in human colonic cell lines LS174T and HM7, by activation of RhoA, Cdc42 and Rac1 in a dose-dependent manner (21). Prostate cancer cell lines DU145 and PC-3 treated with leptin show significantly increased expression of VEGF, TGF-beta1 and bFGF, as well as increased cell migration, which was partially inhibited with the addition of MAPK and PI3K inhibitors (22). There is evidence that leptin also increases integrin expression and migration of prostate cancer cells, by activating the OBR1/IRS-1/PI3K/Akt/NF-kB pathway (23). I can go on and on with different types of cancer  which seem to be promoted by leptin but from the examples above a clear trend can be seen (for a review please refer to 24).

Conclusions

Is leptin just a marker of metabolic diseases or has an active role? From the literature we can see that hyperleptinemia is present in many chronic diseases. Hyperleptinemia is a marker of metabolic dysregulation ie. leptin resistance and inflammation. This does not necessarily imply that leptin is the only factor behind these pathologies, but as a pro-inflammatory cytokine, mediates and exacerbates disease together with other cytokines. This should end the myth of leptin as the "good" or "magic" hormone. Unless there is a leptin deficiency issue, there is no point in trying to increase leptin levels for the sake of increasing them, as it could have negative effects*. As with insulin, low leptin is better than high leptin. And by the way, plasma leptin is directly correlated with plasma insulin (25), so an optimal metabolic mielieu is one in which insulin and leptin are kept low. 


* As for instance, exogenous leptin administration for weight loss in the abscence of leptin deficiency (See 26).

Lago R, Gómez R, Lago F, Gómez-Reino J, & Gualillo O (2008). Leptin beyond body weight regulation--current concepts concerning its role in immune function and inflammation. Cellular immunology, 252 (1-2), 139-45 PMID: 18289518