Neurobiology of Diabetes Research Unit

Aim: To delineate redox-sensitive mechanisms that link environmental changes with the hypothalamic control of energy and glucose homeostasis.

Hypothalamic REDOX Signaling

High-calorie diet exposure, hypo- and hyperthermic conditions, exercise, stress, but also genetic factors modulate the hypothalamic production of reactive oxygen species (ROS) and hypothalamic REDOX signaling. Low levels of ROS are thereby believed to mediate important REDOX signaling events that confer adaptive physiological responses to the environmental stimulus. In contrast, high levels and/or a chronic exposure to environmental stressors lead to excessive ROS production and inflammation, two major hallmarks in the etiology of obesity as well as diabetes type 2.

Fig.: Pfluger

Our group aims to identify novel, earliest REDOX-sensitive signaling events that orchestrate our adaptive response to such environmental changes. Specifically, we aim to evaluate how the REDOX state controls hypothalamic MAPK signaling as well as chaperone and heat shock protein biology. Moreover, we aim to delineate the impact of cellular ROS and REDOX signaling events on chromatin remodeling and the epigenetic control of energy and glucose homeostasis.

In close collaboration with other work groups at the IDO and HMGU we further aim to unravel how chronic oxidative REDOX signals and epigenetic mechanisms impair organelle function e.g. of mitochondria (hyperlink to Martin Jastrochs work group), or cell-cell-communication between neurons, astrocytes and/or microglia (hyperlink to Chun-Xia/Matthias workgroup)).

Nutrient Sensing

Our research further focuses on the role of nutrient sensors in the regulation of energy and glucose homeostasis. In previous studies, we could demonstrate that NAD/NADH sensor Sirtuin1 protects against high-fat diet induced metabolic damage, and identified the novel scaffold protein Ksr2 as essential mediator of AMPK activation. Our recent efforts focus on the physiological roles of the stomach GOAT/ghrelin system. We could discover that the stomach enzyme ghrelin O-acetyltransferase (GOAT), which is essential for ghrelin acylation, acts as lipid sensor to detect the availability of specific fatty acids, rather than their absence. Our current model therefore suggests that acyl ghrelin acts as “nutrikine” to link dietary lipids with energy and glucose metabolism.  Current projects explore potential new roles of desacyl and acyl ghrelin on glucose control.

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