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. ( J. Clin. Invest. 1997. 99:391-395.)

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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 (

Insulin resistance is a feature of many common disorders including obesity and type 2 diabetes mellitus. In these disorders, the ␤-cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity, an increase in ␤-cell mass, or both. To determine whether the ␤-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 ob͞ob mice. In the grafts transplanted into both hosts, there was a marked increase in ␤-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. Many common disorders including obesity, type 2 (noninsulin-dependent) diabetes mellitus, various endocrinopathies, hypertension, and hyperlipidemias are associated with insulin resistance (1-4). In patients with type 2 diabetes, the ␤-cells eventually fail to meet the demand created by the insulin resistance leading to hyperglycemia; however, in most of these disorders, the ␤-cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity, an increase in ␤-cell mass, or both (5-7). Rodent models of diabetes, such as the ob͞ob and db͞db mice and the Zucker fatty rat, and hyperinsulinemic humans with obesity and͞or type 2 diabetes exhibit mild to marked islet hyperplasia at varying times of their disorders (8-12). Likewise, several mouse models of insulin resistance, such as those created by inactivation of the gene for insulin receptor substrate-1 (IRS-1) or double heterozygous (DH) knockout of the insulin receptor and IRS-1, exhibit marked islet hyperplasia (7,13,14).The factors contributing to ␤-cell hyperplasia in insulinresistant states remain poorly understood (15-17). Glucose itself is known to stimulate ␤-cell replication (reviewed in ref. 17); however, DH and IRS-1 knockouts and ob͞ob and db͞db mice all manifest islet hyperplasia before the onset of detectable hyperglycemia (7,14,(18)(19)(20). Furthermore, the hyperplastic response in most cases does not bear a relationship to the level of hyperglycemia, suggesting that factors independent of glucose likely contribute to the islet growth.The aim of the present study was to examine the hypothesis that insulin resistance induces the growth of islet ␤-cells via a circulating mitogenic factor that is independent of glucose and obesity. To test this hypothesis, we adopted a transplantation strategy wherein wild-type (WT) islets were transplanted under the kidney capsule into normoglycemic lean DH mice and obese, hyperglycemic ob͞ob mice with correspon...

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SummaryBackground: Despite advances in treatment, patients with inflammatory bowel dis-

BackgroundThe 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 FindingsTwenty 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).ConclusionsOur 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.

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