Sarah N. Flier

Leptin accelerates the onset of puberty in normal female mice.

The fat-derived hormone, leptin, is proposed to serve as an adipostatic signal to the brain to reduce food intake and body weight. In addition to its effects on body weight, chronic leptin treatment restores puberty and fertility to ob/ob mice with total leptin deficiency, and acute treatment substantially corrects hypogonadism in mice starved for 2 d without affecting body weight. Leptin may therefore be a critical signal, linking adiposity and reproduction. Since body weight and adiposity appear to play a critical role in the timing of puberty in humans and rodents, and leptin levels rise with increasing adiposity, we studied the effects of once daily injections of recombinant leptin on the onset of puberty in female mice weaned on day 21 and fed ad libitum. There was a linear increase in body weight during the study period, which was not altered by the dose of leptin used. Mice injected with leptin had an earlier onset of three classic pubertal parameters (i.e., vaginal opening, estrus, and cycling) compared with saline-injected controls. Leptin is the first peripheral molecule demonstrated to accelerate the maturation of the reproductive axis in normal rodents. We propose that leptin is the signal that informs the brain that energy stores are sufficient to support the high energy demands of reproduction, and may be a major determinant of the timing of puberty.

Altered function of insulin receptor substrate-1–deficient mouse islets and cultured β-cell lines

Insulin receptor substrate-1 (IRS-1) is pivotal in mediating the actions of insulin and growth factors in most tissues of the body, but its role in insulin-producing beta islet cells is unclear. Freshly isolated islets from IRS-1 knockout mice and SV40-transformed IRS-1-deficient beta-cell lines exhibit marked insulin secretory defects in response to glucose and arginine. Furthermore, insulin expression is reduced by about 2-fold in the IRS-1-null islets and beta-cell lines, and this defect can be partially restored by transfecting the cells with IRS-1. These data provide evidence for an important role of IRS-1 in islet function and provide a novel functional link between the insulin signaling and insulin secretion pathways. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Identification of Epithelial to Mesenchymal Transition as a Novel Source of Fibroblasts in Intestinal Fibrosis

Intestinal fibrosis is a major complication of Crohn disease (CD), but the precise mechanism by which it occurs is incompletely understood. As a result, specific therapies to halt or even reverse fibrosis have not been explored. Here, we evaluated the contribution of epithelial to mesenchymal transition (EMT) to intestinal fibrosis associated with a mouse model of CD and also human inflammatory bowel disease. Mice administered intrarectal 2,4,6-trinitrobenzene sulfonic acid (TNBS) develop inflammation and fibrosis that resembles CD both histologically and by immunologic profile. We utilized this model to molecularly probe the contribution of EMT to intestinal fibrosis. Additionally, we utilized double-transgenic VillinCre;R26Rosa-lox-STOP-lox-LacZ mice, in which removal of the STOP cassette by Cre recombinase in villin+ intestinal epithelial cells activates permanent LacZ expression, to lineage trace epithelial cells that might undergo EMT upon TNBS administration. TNBS-induced fibrosis is associated with the presence of a significant number of cells that express both epithelial and mesenchymal markers. In the lineage tagged transgenic mice, the appearance of LacZ+ cells that also express the fibroblast marker FSP1 unequivocally demonstrates EMT. Transforming growth factor (TGF)-β1, a known inducer of EMT in epithelial cells, induces EMT in rat intestinal epithelial cells in vitro, and bone morphogenic protein-7, an antagonist of TGF-β1, inhibits EMT and fibrosis both in vitro and in the TNBS-treated mice. Our study demonstrates that EMT contributes to intestinal fibrosis associated with the TNBS-induced model of Crohn colitis and that inhibition of TGF-β1 with recombinant human bone morphogenic protein-7 prevents this process and prevents fibrosis.

Evidence for a circulating islet cell growth factor in insulin-resistant states

Insulin resistance is a feature of many common disorders including obesity and type 2 diabetes mellitus. In these disorders, the β-cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity, an increase in β-cell mass, or both. To determine whether the β-cell response might relate to a circulating growth factor, we have transplanted normal islets under the kidney capsule of normoglycemic insulin-resistant mice with two different models of insulin resistance: lean mice that have a double heterozygous deletion of the insulin receptor and insulin receptor substrate-1 (DH) or the obese, hyperglycemic ob/ob mice. In the grafts transplanted into both hosts, there was a marked increase in β-cell mitotic activity and islet mass that was comparable with that observed in the endogenous pancreas. By contrast, islets of the DH mouse transplanted into normal mice showed reduced mitotic index. These data suggest the insulin resistance is associated with a circulating islet cell growth factor that is independent of glucose and obesity.

Is functional dyspepsia of particular concern in women? A review of gender differences in epidemiology, pathophysiologic mechanisms, clinical presentation, and management

Dyspepsia is a remarkably common symptom in the general population. Although multiple definitions have been used to describe the symptom, the most common explanation is that of chronic or recurrent pain or discomfort (a subjective negative feeling that may be associated with early satiety, fullness, bloating, or nausea) centered in the upper abdomen. When a thorough evaluation of a dyspeptic patient fails to identify a cause for her symptoms, the label of nonulcer or functional dyspepsia is applied. Functional dyspepsia is a heterogeneous disorder characterized by relapsing and remitting symptoms. Treatment strategies should focus on alleviating the most bothersome symptom and can be based on the proposed underlying pathophysiology. The effect of gender on mechanisms of disease, symptom presentation, and treatment response is an area of increasing interest and study. As with other functional gastrointestinal disorders, there appear to be some gender-specific features of functional dyspepsia. Specifically, gender-related differences have been observed in some studies of both the prevalence of individual dyspepsia symptoms, and in gastric emptying and proximal gastric motor function. There also appear to be gender differences in the psychosocial realm, with dyspeptic women experiencing a lesser sense of well-being than dyspeptic men, as well as an association of an abuse history with functional dyspepsia. This review will highlight specific gender differences related to the symptom presentation, pathophysiology, and approach to treatment of functional dyspepsia, while noting where differences have not been found and where further investigation is warranted.

A case confirming the progressive stages of pyomyositis

A teenage boy presented in the early stage of pyomyositis. He had neck pain, tenderness, and fever. A computed tomography scan showed inflammation in the sternocleidomastoid muscle with no fluid collection. This progressed to a pus-filled drainable mass caused by Stapylococcus aureus. The authors describe this case to highlight the predictable stages and increase the index of suspicion to enhance its early recognition.

Contribution of Epithelial Plasticity to Renal Transplantation–Associated Fibrosis

Every year in the United States, 5000 renal transplant recipients start or restart dialysis because of the unusual propensity of these allografts to develop interstitial fibrosis and tubular atrophy (IF/TA). Although IF/TA often follows one or more identifiable events, our capacity to specifically treat, prevent, or even detect IF/TA at an early stage is poor. These limitations are largely related to our lack of adequate tools to assess graft failure over time. Data accumulated over the past 5 years have demonstrated that tubular epithelial cells may react to certain fibrogenic stimuli to engage in the process of epithelial-to-mesenchymal transition (EMT). In this review, we highlight the current view of EMT with a focus on both its role in the context of renal transplantation and the potential for utilizing markers of EMT to identify patients undergoing early IF/TA.

Elevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis

Background The metabolic regulator Fibroblast Growth Factor 21 (FGF21) is highly expressed in the acinar pancreas, but its role in pancreatic function is obscure. It appears to play a protective role in acute experimental pancreatitis in mice. The aim of this study was to define an association between FGF21 and the course and resolution of acute pancreatitis in humans. Methods and Principal Findings Twenty five subjects with acute pancreatitis admitted from May to September 2012 to the Beth Israel Deaconess Medical Center (BIDMC) were analyzed. Serial serum samples were collected throughout hospitalization and analyzed for FGF21 levels by ELISA. Twenty healthy subjects sampled three times over a four week period were used as controls. We found that, in patients with pancreatitis, serum FGF21 rises significantly and peaks four to six days after the maximum lipase level, before slowly declining. Maximum FGF21 levels were significantly greater than baseline levels for acute pancreatitis subjects (1733 vs. 638 pg/mL, P = 0.003). This maximum value was significantly greater than the highest value observed for our control subjects (1733 vs. 322 pg/mL, P = 0.0002). The ratio of active to total FGF21 did not change during the course of the disease (42.5% vs. 44.4%, P = 0.58). Fold increases in FGF21 were significantly greater in acute pancreatitis subjects than the fold difference seen in healthy subjects (4.7 vs. 2.0, P = 0.01). Higher fold changes were also seen in severe compared to mild pancreatitis (18.2 vs. 4.4, P = 0.01). The timing of maximum FGF21 levels correlated with day of successful return to oral intake (R2 = 0.21, P = 0.04). Conclusions Our results demonstrate that serum FGF21 rises significantly in humans with acute pancreatitis. The pancreas may be contributing to increased FGF21 levels following injury and FGF21 may play a role in the recovery process.

Are Expectations Too High for Transitioning Adolescents With Inflammatory Bowel Disease? Examining Adult Medication Knowledge and Self-management Skills

Objective: Transition readiness assessment has focused attention on adolescent knowledge and skills, but data-driven benchmarks have not been established. Methods: Patients with inflammatory bowel disease (IBD), ages 25 to 50 years, attending an outpatient gastroenterology clinic, were recruited to complete a voluntary, confidential survey asking patients to recall medications and potential side effects, and to rate their degree of independence performing health maintenance tasks. Results: The 141 respondents (48% response rate) had mean age of 36 years with median disease duration of 11 years. They were 60% female, 54% had Crohn disease, and 23% were diagnosed before age 18. Nearly all patients were fully independent answering doctors questions during the visit (93%) and scheduling office visits (92%). Excluding pharmacy pick up, full independence seen in only 57%, whereas 16% significantly delegated tasks. No differences by sex, disease type, medication class, age at disease onset, or disease duration were found across levels of self-management. Almost all (97%) respondents could recall medication name, whereas fewer were able to recall dose (63%) or frequency (65%). Side effect knowledge was poor; among 81 patients on a biologic or immunomodulator, only 17 (21%) cited cancer and 22 (27%) cited infection. Conclusions: Adolescent IBD transition programs now have empirical data from the present study about adult benchmarks for independence in self-management skills. Further research can establish which skills correlate with medication adherence and active collaboration with the medical team. The present study also exposes important gaps in medication risk knowledge and may allow improved patient education for subgroups of adult patients with IBD.

Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis

Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-β on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD.