Fibroblast growth factor-21 (FGF-21) is a recently discovered metabolic regulator. Here, we investigated the effects of FGF-21 in the pancreatic ␤-cell. In rat islets and INS-1E cells, FGF-21 activated extracellular signal-regulated kinase 1/2 and Akt signaling pathways. In islets isolated from healthy rats, FGF-21 increased insulin mRNA and protein levels but did not potentiate glucose-induced insulin secretion. Islets and INS-1E cells treated with FGF-21 were partially protected from glucolipotoxicity and cytokineinduced apoptosis. In islets isolated from diabetic rodents, FGF-21 treatment increased islet insulin content and glucose-induced insulin secretion. Short-term treatment of normal or db/db mice with FGF-21 lowered plasma levels of insulin and improved glucose clearance compared with vehicle after oral glucose tolerance testing. Constant infusion of FGF-21 for 8 weeks in db/db mice nearly normalized fed blood glucose levels and increased plasma insulin levels. Immunohistochemistry of pancreata from db/db mice showed a substantial increase in the intensity of insulin staining in islets from FGF-21-treated animals as well as a higher number of islets per pancreas section and of insulin-positive cells per islet compared with control. No effect of FGF-21 was observed on islet cell proliferation. In conclusion, preservation of ␤-cell function and survival by FGF-21 may contribute to the beneficial effects of this protein on glucose homeostasis observed in diabetic animals. Diabetes 55:2470 -2478, 2006 P ancreatic ␤-cell dysfunction is a central component of the pathogenesis of all forms of diabetes. Type 1 diabetes manifests from the autoimmune destruction of ␤-cells, whereas type 2 diabetes is characterized by reduced ␤-cell mass and marked functional defects, including impaired first-phase insulin secretion, increased proinsulin-to-insulin ratio, and elevated rate of ␤-cell apoptosis (1-3). The glucose-sensing and insulin-signaling pathways have been shown to play important roles in insulin secretion as well as ␤-cell growth and survival. For example, mice lacking insulin receptors, insulin receptor substrate-2, or Akt (protein kinase B) display marked defects in glucose sensing, insulin secretion, and ␤-cell mass (4 -6). The amount of secreted insulin is determined by the secretory activity of the ␤-cell and the total number of ␤-cells in the pancreas. Glucose plays an essential role in the control of secretory activity of ␤-cells. Metabolism of glucose leads to an increase in the ATP-to-ADP ratio, membrane depolarization, Ca 2ϩ influx, and stimulation of insulin secretion (7). ␤-Cell mass is governed by the balance between ␤-cell growth and ␤-cell death (apoptosis). Type 2 diabetic patients display a progressive loss of ␤-cells caused by an increased rate of ␤-cell apoptosis (8). However, the cause and mechanism(s) responsible for the increased apoptosis rate in type 2 diabetes are not well understood (9). Preventing ␤-cell death and increasing survival of the ␤-cell can be a valuable therapeutic approa...

Mice deficient for the major lysosomal aspartic proteinase cathepsin D, generated by gene targeting, develop normally during the first 2 weeks, stop thriving in the third week and die in a state of anorexia at day 26 +/− 1. An atrophy of the ileal mucosa first observed in the third week progresses towards widespread intestinal necroses accompanied by thromboemboli. Thymus and spleen undergo massive destruction with fulminant loss of T and B cells. Lysosomal bulk proteolysis is maintained. These results suggest, that vital functions of cathepsin D are exerted by limited proteolysis of proteins regulating cell growth and/or tissue homeostasis, while its contribution to bulk proteolysis in lysosomes appears to be non‐critical.

Lipoprotein lipase (LPL) is a key regulator of triglyceride clearance. Its coordinated regulation during feeding and fasting is critical for maintaining lipid homeostasis and energy supply. Angiopoietin-like (Angptl)3 and Angptl4 are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angptl4- and Angptl3-deficient mice as well as transgenic mice overexpressing human Angptl4 in the liver. The Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma (PHP) LPL activity. A purified recombinant Angptl4 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angptl4-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angptl3-deficient mice also displayed hypotriglyceridemia with elevated PHP LPL activity, but these mice showed a greater effect in the fed state. Mice deficient in both Angptl proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angptl3 and Angptl4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.

Summary Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we show that the lipoprotein lipase inhibitor Angptl4 protects against the pronounced pro-inflammatory effects of dietary saturated fat. Strikingly, in mice lacking Angptl4, dietary saturated fat induces a severe and ultimately lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in the mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced macrophage foam cell formation, inflammatory gene expression, and chyle-induced activation of the ER stress pathway. The data reveal a novel mechanism in which induction of macrophage Angptl4 by fatty acids serves to reduce postprandial lipid uptake from fatty chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled dietary saturated fat-induced inflammation.

The neuropeptide orphanin FQ (also known as nociceptin; OFQ͞N) has been implicated in modulating stress-related behavior. OFQ͞N was demonstrated to reverse stress-induced analgesia and possess anxiolytic-like activity after central administration. To further study physiological functions of OFQ͞N, we have generated OFQ͞N-deficient mice by targeted disruption of the OFQ͞N gene. Homozygous mice display increased anxiety-like behavior when exposed to a novel and threatening environment. OFQ͞N-null mice show elevated basal pain threshold but develop normal stressinduced analgesia. Interestingly, these mice show impaired adaptation to repeated stress when compared with wild-type mice, whereas their performance in spatial learning remained unaffected. Basal and poststress plasma corticosterone levels were found to be elevated in OFQ͞N-deficient animals. Thus, OFQ͞N appears to be crucially involved in the neurobiological regulation of stress-coping behavior and fear.Physiological responses to stress include changes in behavior, sensory processing, and endocrine and metabolic homeostasis that are positively or negatively regulated by a multitude of neuronal pathways (1-7). An increased vulnerability to stress is discussed as a major contributing factor in human psychiatric disorders, such as anxiety and depression (8). At the hormonal level, these diseases often are accompanied by an overactivity of the hypothalamic-pituitary-adrenal (HPA) system (9, 10). However, the physiological basis for this dysregulation remains unclear. The recently discovered neuropeptide OFQ͞N (11, 12) appears to alleviate behavioral and sensory responses to stress, such as fear responses (13) or analgesia (14). Further studies on the functions of OFQ͞N in the neuronal processing of stress are hampered by the unavailability of a selective and high-affinity antagonist. Therefore, we took a genetic approach and generated OFQ͞N-deficient mice that were analyzed for phenotypical differences in stress-related responses. The absence of OFQ͞N increases stress-related variables of behavior and sensory processing, such as anxiety and nociceptive threshold, in genetically engineered mice. Mice lacking OFQ͞N show elevated glucocorticoid levels, indicating a chronic activation of the HPA system that might contribute to the observed phenotypic changes. In addition, an important function of OFQ͞N for stress adaptation was discovered, because OFQ͞N-deficient mice failed to habituate after repeated exposure to stressful stimuli. These results suggest that the OFQ͞N system may have important functions in the neural circuitry of stress processing.