Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis.

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

Band-like arrangement of taste-like sensory cells at the gastric groove: evidence for paracrine communication.

The discovery of taste-related elements within the gastrointestinal tract has led to a growing interest in the mechanisms and physiological significance of chemosensory monitoring of chymus composition. Previous work suggests that brush cells located in the "gastric groove," which parallels the "limiting ridge," a structure in rodents that divides the fundus from the corpus, are candidate sensory cells. A novel sectioning technique revealed that these cells are arranged in a palisade-like manner forming a band which borders the whole length of the corpus epithelium. Using transgenic PLCß2 promoter-GFP mice and specific antibodies, we have demonstrated that most of these cells express gustducin, PLCß2, and TRPM5; typical signaling proteins of gustatory sensory "type II" cells. These molecular features strongly suggest that the cells may be capable of sensing nutrient or non-nutrient constituents of the ingested food. Since there is no evidence that brush cells are endocrine cells, attempts were made to explore how such putative chemosensory cells might transmit the information to "effector" cells. It was found that most of the cells express the neuronal nitric oxide synthase (NOS) suggesting some paracrine interaction with adjacent cells. Moreover, they also express choline acetyltransferase (ChAT) as well as the vesicular protein SNAP25, indicating the potential for cholinergic transmission, possibly with subjacent enteric nerve fibers.