Flo progressive weight gain 2017
Although inflammation is sufficient to induce anorexia, the increased food intake during LCN2 blockade is independent of systemic inflammatory state and immunologic activation. Importantly, we detect LCN2 in the brain after restoring expression in the bone marrow compartment, demonstrating LCN2 readily crosses the blood–brain barrier (BBB). We show that the genetic deletion of Lcn2 mitigates cachexia–anorexia and lean and fat mass loss, while restoration of LCN2 in the bone marrow compartment alone reestablishes the anorexia and muscle catabolism features of cachexia. Since the literature supports the notion that Lcn2 tissue expression is disease-dependent 11, we identify the bone marrow and myeloid compartment, namely neutrophils, as the predominant source of LCN2 during pancreatic cancer cachexia. In five separate rodent models of pancreatic cancer cachexia, we demonstrate a large induction of circulating and central LCN2 levels that negatively correlate with food intake and muscle mass. Here, we explore the relationship between LCN2 production, feeding behaviors, and tissue catabolism during pancreatic cancer cachexia.
However, whether the dysregulation of LCN2 produces meaningful changes in energy balance during cancer-associated cachexia is not known. These studies demonstrate a role for LCN2 in regulating appetite during non-pathologic states. Recently published data demonstrate LCN2 suppresses appetite through its binding to the melanocortin 4 receptor (MC4R) in the paraventricular nucleus (PVN) of the hypothalamus 15, a nucleus essential in regulating feeding behaviors and energy homeostasis 16. Lipocalin 2 (LCN2), also known as neutrophil gelatinase-associated lipocalin, siderocalin, or 24p3, is a pleiotropic mediator of several inflammatory and metabolic processes that is secreted into circulation during a variety of diseases associated with cachexia 11, including cancer 12, chronic kidney disease 13, and heart failure 14. To this end, significant efforts are being made to identify the mechanism of appetite dysregulation during cancer-associated cachexia. Therefore, identification of the pathways that influence nutritional deficits associated with cachexia could provide new therapeutic options for this otherwise debilitating metabolic disorder. Indeed, nutritional interventions and pharmacologic improvement of appetite are emerging as promising treatment paradigms for patients with cachexia 8, 9, 10. Since decreased nutrition is an essential component of cancer cachexia 6, 7, improving cachexia-related anorexia remains an important aspect in treating this metabolic disorder. This mismatch in caloric intake and expenditure imposes a significant energy imbalance, leading to excessive wasting, reduced quality of life, and decreased patient tolerance to therapy 4, 5. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.Ĭachexia, or disease-associated wasting, is a metabolic state consisting of a paradoxical decrease in appetite, yet increase in basal metabolic rate 1, 2, 3.
Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Consistent with LCN2’s proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting.
Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite.