Biomedical subjects

Atsuo T Sasaki

Publications and source records attributed to Atsuo T Sasaki.

5 recordsLinked to original sources

PubMed2026

Deletion of neurosecretory proteins GL and GM drives dual anti-obesity effects via appetite suppression and enhanced energy expenditure.

Obesity results from an imbalance between energy intake and expenditure and is regulated by hypothalamic neuropeptide systems. The neurosecretory proteins GL (NPGL) and GM (NPGM) are expressed in the hypothalamus and promote feeding in gain-of-function studies; however, their endogenous physiological roles remain unclear. Here, we show that mice lacking both NPGL and NPGM display a lean phenotype driven by reduced food intake and increased energy expenditure. This anti-obesity phenotype is associated with increased expression of anorexigenic pro-opiomelanocortin in the hypothalamus and enhanced thermogenic activity in brown adipose tissue, marked by elevated uncoupling protein 1. Consistent with these findings, suppression of NPGL/NPGM signaling reduces feeding and alters sympathetic nerve activity. In addition, genome-wide association analysis identifies an obesity-associated variant near the human NPGM locus, suggesting relevance to human energy balance. Together, these findings identify NPGL and NPGM as endogenous regulators of energy homeostasis with potential relevance to obesity.

Animals↗

PubMed2006

Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR.

Directed cell migration and cell polarity are crucial in many facets of biological processes. Cellular motility requires a complex array of signaling pathways, in which orchestrated cross-talk, a feedback loop, and multi-component signaling recur. Almost every signaling molecule requires several regulatory processes to be functionally activated, and a lack of a signaling molecule often leads to chemotaxis defects, suggesting an integral role for each component in the pathway. We outline our current understanding of the signaling event that regulates chemotaxis with an emphasis on recent findings associated with the Ras, PI3K, and target of rapamycin (TOR) pathways and the interplay of these pathways. Ras, PI3K, and TOR are known as key regulators of cellular growth. Deregulation of those pathways is associated with many human diseases, such as cancer, developmental disorders, and immunological deficiency. Recent studies in yeast, mammalian cells, and Dictyostelium discoideum reveal another critical role of Ras, PI3K, and TOR in regulating the actin cytoskeleton, cell polarity, and cellular movement. These findings shed light on the mechanism by which eukaryotic cells maintain cell polarity and directed cell movement, and also demonstrate that multiple steps in the signal transduction pathway coordinately regulate cell motility.

Actin-Related Protein 2-3 Complex↗

PubMed2005

Rho Rocks PTEN.

Explore the source record for details and available documents.

Animals↗

PubMed2005

Finding the way: directional sensing and cell polarization through Ras signalling.

Chemotactic eukaryotic cells have the unique ability to sense a shallow extracellular chemoattractant gradient and translate it into a steep intracellular gradient. For example, phosphoinositide-3,4,5-trisphosphate (PIP3), the product of phosphatidylinositol-3-kinase (PI3K), is accumulated at the leading edge but not the back of a polarized chemotaxing cell. This is partially controlled by the reciprocal, preferential localization of PI3K and PTEN to the membrane at the front and back, respectively. However, upstream events that control the localized activation and localization of PI3K and PTEN remain unclear. Recent findings indicate that Ras is important for activation of the PI3K pathway and regulation of directed cell movement and cell polarity. Ras is activated at the leading edge, and this local activation occurs without asymmetric localization of PI3K and PTEN or the F-actin cytoskeleton. In contrast, P13K localization is driven by F-actin polymerization. Thus, Ras functions as an essential part of the cell's compass acting upstream of PI3K while reciprocal localization of PI3K and PTEN amplify the PIP3 gradient, rather than create it. These observations suggest a positive feedback loop to amplify an initial PIP3 gradient in which localized F-actin polymerization recruits cytosolic PI3K to the leading edge, where it is activated by Ras to locally produce PIP3 that induces F-actin polymerization.

Animals↗

PubMed2004

Localized Ras signaling at the leading edge regulates PI3K, cell polarity, and directional cell movement.

During chemotaxis, receptors and heterotrimeric G-protein subunits are distributed and activated almost uniformly along the cell membrane, whereas PI(3,4,5)P(3), the product of phosphatidylinositol 3-kinase (PI3K), accumulates locally at the leading edge. The key intermediate event that creates this strong PI(3,4,5)P(3) asymmetry remains unclear. Here, we show that Ras is rapidly and transiently activated in response to chemoattractant stimulation and regulates PI3K activity. Ras activation occurs at the leading edge of chemotaxing cells, and this local activation is independent of the F-actin cytoskeleton, whereas PI3K localization is dependent on F-actin polymerization. Inhibition of Ras results in severe defects in directional movement, indicating that Ras is an upstream component of the cell's compass. These results support a mechanism by which localized Ras activation mediates leading edge formation through activation of basal PI3K present on the plasma membrane and other Ras effectors required for chemotaxis. A feedback loop, mediated through localized F-actin polymerization, recruits cytosolic PI3K to the leading edge to amplify the signal.

Actins↗