Leptin, Estrogen, Inflammation, Breast Cancer

Also see:
Sugar (Sucrose) Restrains the Stress Response
Endotoxin: Poisoning from the Inside Out
Ray Peat, PhD on Endotoxin
Hormonal profiles in women with breast cancer
Plasma Estrogen Does Not Reflect Tissue Concentration of Estrogen
Pre and Postmenopausal Women: Progesterone Decreases Aromatase Activity
Fat Tissue and Aging – Increased Estrogen
Estrogen Related to Loss of Fat Free Mass with Aging
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
Breast Cancer by Ray Peat
Preventing and treating cancer with progesterone by Ray Peat

Quotes by Ray Peat, PhD:
“I doubt that there is any biological significance in the idea of leptin resistance. Leptin promotes inflammation and cancer, so it might be good to be resistant to it, but I think the concept is mainly an outgrowth of the pharmaceutical industry’s promotion of leptin as a cure for obesity.”

Progesterone opposes those various biochemical effects of estrogen in multiple ways, for example by inhibiting the ACTH stress response, by restraining cortisol’s harmful actions, and by inhibiting leptin.”

Cell Immunol. 2008 Mar-Apr;252(1-2):139-45. doi: 10.1016/j.cellimm.2007.09.004. Epub 2008 Mar 4.
Leptin beyond body weight regulation–current concepts concerning its role in immune function and inflammation.
Lago R, Gómez R, Lago F, Gómez-Reino J, Gualillo O.
Leptin, a 16 kDa non-glycosylated polypeptide produced primarily by adipocytes and released into the systemic circulation, exerts a multitude of regulatory functions including energy utilization and storage, regulation of various endocrine axes, bone metabolism, and thermoregulation. In addition to leptin’s best known role as regulator of energy homeostasis, several studies indicate that leptin plays a pivotal role in immune and inflammatory response. Because of its dual nature as a hormone and cytokine, leptin can be nowadays considered the link between neuroendocrine and immune system. The increase in leptin production that occurs during infections and inflammatory processes strongly suggests that this adipokine is a part of the cytokines network which governs inflammatory/immune response and host defence mechanisms. Indeed, leptin plays a relevant role in inflammatory processes involving either innate or adaptive immune responses. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as encephalomyelitis, type I diabetes, bowel inflammation and also articular degenerative diseases such as rheumatoid arthritis and osteoarthritis. Although the mechanisms by which leptin exerts its action as modulator of inflammatory/immune response are likely to be more complex than predicted and far to be completely depicted, there is a general consensus about its pivotal role as pro-inflammatory and immune-modulating agent. Here, we review the most recent advances on leptin biology with a particular attention to its adipokine facet, even though its role as metabolic hormone will be also addressed.

Mol Cell Endocrinol. 2013 Apr 4. pii: S0303-7207(13)00121-4. doi: 10.1016/j.mce.2013.03.025. [Epub ahead of print]
Leptin-cytokine crosstalk in breast cancer.
Newman G, Gonzalez-Perez RR.
Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman’s laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously decreased the levels of VEGF/VEGFR2, IL-1 and Notch. Inhibition of leptin-cytokine crosstalk might serve as a preventative or adjuvant measure to target breast cancer, particularly in obese women. This review is intended to present an update analysis of leptin actions in breast cancer, highlighting its crosstalk to inflammatory cytokines and growth factors essential for tumor development, angiogenesis and potential role in BCSC.

Pathol Oncol Res. 2006;12(2):69-72. Epub 2006 Jun 24.
Leptin–from regulation of fat metabolism to stimulation of breast cancer growth.
Sulkowska M, Golaszewska J, Wincewicz A, Koda M, Baltaziak M, Sulkowski S.
Leptin restricts intake of calories as a satiety hormone. It probably stimulates neoplastic proliferation in breast cancer, too. Growth of malignant cells could be regulated by various leptin-induced second messengers like STAT3 (signal transducers and activators of transcription 3), AP-1 (transcription activator protein 1), MAPK (mitogen-activated protein kinase) and ERKs (extracellular signal-regulated kinases). They seem to be involved in aromatase expression, generation of estrogens and activation of estrogen receptor alpha (ERalpha) in malignant breast epithelium. Leptin may maintain resistance to antiestrogen therapy. Namely, it increased activation of estrogen receptors, therefore, it was suspected to reduce or even overcome the inhibitory effect of tamoxifen on breast cell proliferation. Although several valuable reviews have been focused on the role of leptin in breast cancer, the status of knowledge in this field changes quickly and our insight should be continuously revised. In this summary, we provide refreshed interpretation of intensively reported scientific queries of the topic.

J Cell Biochem. 2008 Nov 1;105(4):956-64. doi: 10.1002/jcb.21911.
Leptin signaling in breast cancer: an overview.
Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N.
The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.

Mini Rev Med Chem. 2006 Aug;6(8):897-907.
Leptin, estrogens and cancer.
Maeso Fortuny MC, Brito Díaz B, Cabrera de León A.
Obesity is a state of leptin resistance in which the membrane leptin receptor and the JAK-STAT pathway are blocked. This leads to increased intracellular concentrations of lipid metabolites, increased non-oxidative metabolism by adipocytes, and stimulation of the cell estrogen cycle. These factors are potentially oncogenic via the shared mitogen-activated protein kinase (MAPK), mitogen/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK) cellular pathways.

Expert Opin Investig Drugs. 2005 Mar;14(3):251-64.
Parathyroid hormone and leptin–new peptides, expanding clinical prospects.
Whitfield JF.
Leptin, a member of the cytokine superfamily has a PTH-like osteogenic activity and may even partly mediate PTH action. But leptin has two drawbacks that cloud its therapeutic future. First, apart from directly stimulating osteoblastic cells, it targets cells in the hypothalamic ventromedial nuclei and through them it reduces oestrogenic activity by promoting osteoblast-suppressing adrenergic activity. Second, it stimulates vascular and heart valve ossification, which leads to such events as heart failure and diabetic limb amputations.

Endocrinology 2001 Jul;142(7):2796-804.
Sucrose ingestion normalizes central expression of corticotropin-releasing-factor messenger ribonucleic acid and energy balance in adrenalectomized rats: a glucocorticoid-metabolic-brain axis?
Laugero KD, Bell ME, Bhatnagar S, Soriano L, Dallman MF.
Both CRF and norepinephrine (NE) inhibit food intake and stimulate ACTH secretion and sympathetic outflow. CRF also increases anxiety; NE increases attention and cortical arousal. Adrenalectomy (ADX) changes CRF and NE activity in brain, increases ACTH secretion and sympathetic outflow and reduces food intake and weight gain; all of these effects are corrected by administration of adrenal steroids. Unexpectedly, we recently found that ADX rats drinking sucrose, but not saccharin, also have normal caloric intake, metabolism, and ACTH. Here, we show that ADX (but not sham-ADX) rats prefer to consume significantly more sucrose than saccharin. Voluntary ingestion of sucrose restores CRF and dopamine-beta-hydroxylase messenger RNA expression in brain, food intake, and caloric efficiency and fat deposition, circulating triglyceride, leptin, and insulin to normal. Our results suggest that the brains of ADX rats, cued by sucrose energy (but not by nonnutritive saccharin) maintain normal activity in systems that regulate neuroendocrine (hypothalamic-pituitary-adrenal), behavioral (feeding), and metabolic functions (fat deposition). We conclude that because sucrose ingestion, like glucocorticoid replacement, normalizes energetic and neuromodulatory effects of ADX, many of the actions of the steroids on the central nervous system under basal conditions may be indirect and mediated by signals that result from the metabolic effects of adrenal steroids.

Ginekol Pol. 1999 Jan;70(1):1-7.
Leptin regulation of aromatase activity in adipose stromal cells from regularly cycling women.
Magoffin DA, Weitsman SR, Aagarwal SK, Jakimiuk AJ.
OBJECTIVES AND DESIGN:
Leptin, a product of adipocytes, is a cytokine with multiple effects on the reproductive axis. Leptin causes the activation of STAT proteins within target cells. The aromatase gene promoter in adipose stromal cells contains a functional STAT binding region, leading to the hypothesis that leptin may regulate aromatase activity in fat tissue. To test this hypothesis, adipose stromal cells were isolated from subcutaneous abdominal fat or breast fat then placed into tissue culture.
MATERIALS AND METHODS:
The cells were treated for three days with increasing concentrations of recombinant human leptin. Aromatase activity in the stromal cells was measured by the release of 3H2O from radiolabeled androstenedione precursor.
RESULTS:
Basal aromatase activity varied markedly between, but there were no differences between abdominal fat and breast fat. Leptin concentrations in the physiological range of normal weight or thin women (10 ng/ml) had no effect on aromatase activity. In 2 of 8 abdominal fat cultures and 1 of 2 breast fat cultures, a high obese concentration of leptin (100 ng/ml) stimulated a significant increase in aromatase activity. In the remaining subjects there was no effect of leptin, even at high concentrations.
CONCLUSIONS:
These data demonstrate that in approximately 30 percent of our subject population leptin was able to stimulate aromatase activity in adipose stromal cells at high concentrations. The elevated levels of aromatase activity may contribute to increase circulating estrogen levels in certain obese women and suggest that elevated leptin concentrations in obese women may cause locally elevated estrogen concentrations in the breast and thereby promote tumor formation.

Contrib Nephrol. 2006;151:151-64.
Leptin as a proinflammatory cytokine.
Lord GM.
Leptin is a 16-kDa protein produced mainly by adipocytes. Animal models demonstrate that leptin is required for control of bodyweight and reproduction, since mice defective in leptin or the leptin receptor are obese, hyperphagic insulin resistant and infertile. Our initial series of observations lead us to propose that leptin also had significant effects on human type I proinflammatory immune responses. In support of this hypothesis, leptin deficient mice are resistant to a wide range of autoimmune diseases and display features of immune deficiency. Subsequent work has confirmed that leptin has a pleiotrophic role on the immune response and can rightly be considered, both structurally and functionally, as a proinflammatory cytokine.

Fertil Steril. 2010 Aug;94(3):1037-43.
Serum leptin levels, hormone levels, and hot flashes in midlife women.
Alexander C, Cochran CJ, Gallicchio L, Miller SR, Flaws JA, Zacur H.
To examine the associations between serum leptin levels, sex steroid hormone levels, and hot flashes in normal weight and obese midlife women.
DESIGN:
Cross-sectional study.
SETTING:
University clinic.
PATIENT(S):
201 Caucasian, nonsmoking women aged 45 to 54 years with a body mass index of <25 kg/m2 or >or=30 kg/m2.
INTERVENTION(S):
Questionnaire, fasting blood samples.
MAIN OUTCOME MEASURE(S):
Serum leptin and sex steroid hormone levels.
RESULT(S):
Correlation and regression models were performed to examine associations between leptin levels, hormone levels, and hot flashes. Leptin levels were associated with BMI, with “ever experiencing hot flashes” (questionnaire), with hot flashes within the last 30 days, and with duration of hot flashes (>1 year, P=.03). Leptin was positively correlated with testosterone, free testosterone index, and free estrogen index and inversely associated with levels of sex hormone-binding globulin. In women with a body mass index>or=30 kg/m2, leptin levels no longer correlated with testosterone levels.
CONCLUSION(S):
Serum leptin levels are associated with the occurrence and duration of hot flashes in midlife women; however, no correlation was found between leptin and serum estradiol.

Endocr Relat Cancer. 2010 Apr 21;17(2):373-82.
Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting.
Fusco R, Galgani M, Procaccini C, Franco R, Pirozzi G, Fucci L, Laccetti P,
Matarese G.
Obesity is associated with an increased risk of breast cancer. A number of adipocytokines are increased in obesity causing low-level chronic inflammation associated with an increased risk of tumors. The adipocytokine leptin shows profound anti-obesity and pro-inflammatory activities. We have hypothesized that in common obesity, high circulating leptin levels might contribute to an increased risk of breast cancer by affecting mammary cell proliferation and survival. Leptin exerts its activity not only through leptin receptor (LepR), but also through crosstalk with other signaling systems implicated in tumorigenesis. In this study, we focused our attention on the relationship between the leptin/LepR axis and the estrogen receptor-alpha (ERalpha). To this aim, we utilized two human breast cancer cell lines, one ERalpha-positive cell line (MCF 7) and the other ERalpha-negative cell line (MDA-MB 231). We observed that the two cell lines had a different sensitivity to recombinant leptin (rleptin): on MCF 7 cells, rleptin induced a strong phosphorylation of the signal transducer and activator of transcription (STAT) 3 and of the extracellular related kinase 1/2 pathways with an increased cell viability and proliferation associated with an increased expression of ERalpha receptor. This response was not present in the MDA-MB 231 cells. The effects induced by leptin were lost when LepR was neutralized using either a monoclonal inhibitory antibody to LepR or LepR gene-silencing siRNA. These data suggest that there is a bidirectional communication between LepR and ERalpha, and that neutralization and/or inactivation of LepR inhibits proliferation and viability of human breast cancer cell lines. This evidence was confirmed by ex vivo studies, in which we analyzed 33 patients with breast cancer at different stages of disease, and observed that there was a statistically significant correlation between the expression of LepR and ERalpha. In conclusion, this study suggests a crosstalk between LepR and ERalpha, and could envisage novel therapeutic settings aimed at targeting the LepR in breast cancers.

J Clin Endocrinol Metab. 2003 Mar;88(3):1285-91.
Endotoxin stimulates leptin in the human and nonhuman primate.
Landman RE, Puder JJ, Xiao E, Freda PU, Ferin M, Wardlaw SL.
Leptin, which plays a key role in regulating energy homeostasis, may also modulate the inflammatory response. An inflammatory challenge with endotoxin has been shown to stimulate leptin release in the rodent. This finding has not been reproduced in humans or in nonhuman primates, although leptin levels have been reported to increase in septic patients. We have therefore examined the effects of endotoxin injection on plasma leptin levels in nine ovariectomized monkeys and four postmenopausal women. In an initial study in five monkeys, mean leptin levels did not increase during the first 5 h after endotoxin treatment, but did increase significantly from 6.4 +/- 2.1 ng/ml at baseline to 12.3 +/- 4.4 ng/ml at 24 h (P = 0.043). In a second study, a significant increase in leptin over time was noted after endotoxin treatment (P < 0.001); leptin release during the 16- to 24-h period after endotoxin injection was 48% higher than during the control period (P = 0.043). A similar stimulatory effect of endotoxin on leptin was observed when monkeys received estradiol replacement. In a third study, repeated injections of endotoxin over a 3-d period stimulated IL-6, ACTH, cortisol, and leptin release (P < 0.001). Leptin increased during the first day of treatment in all animals, but only monkeys with baseline plasma leptin levels greater than 10 ng/ml exhibited a sustained increase in leptin throughout the 3-d period. There was a significant correlation (r = 0.81; P = 0.008) between the mean baseline leptin level and the percent increase in leptin over baseline on the last day of treatment. In the human subjects, plasma leptin concentrations did not change significantly during the 7-h period after endotoxin injection. However, leptin increased in all four women from a mean baseline of 8.34 +/- 3.1 to 13.1 +/- 4.3 ng/ml 24 h after endotoxin (P = 0.038). In summary, endotoxin stimulates the release of leptin into peripheral blood in the human and nonhuman primate, but the time course is different from that reported in the rodent. These results are consistent with previous reports of increased blood leptin levels in patients with sepsis. The significance of these findings and the potential role of leptin in modulating the response to inflammation in the human require further study.

J Leukoc Biol. 2000 Oct;68(4):437-46.
Leptin in the regulation of immunity, inflammation, and hematopoiesis.
Fantuzzi G, Faggioni R.
Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.

Exp Clin Endocrinol Diabetes. 1999;107(2):119-25.
Mechanisms of TNF-alpha-induced insulin resistance.
Hotamisligil GS.
There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha’s promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.