CNS & glucose control

Hypothalamic MAPK signaling in the etiology of obesity and diabetes type 2

Obesity is the major risk factor for the development of diabetes type 2; increased levels of circulating fatty acids and/or adipocytokines are thereby thought to activate MAP Kinases (MAPK) such as the c-Jun NH2-terminal kinase (JNK) in multiple tissues, including hypothalamic nuclei. MAPK activation in turn is known to escalate canonical immune responses, leading to multiple sequelæ such as the development of insulin resistance and diabetes type 2. Recent GWAS studies identified several MAPK-modulatory proteins as potential novel diabetes type 2 risk genes. We are interested in GWAS-identified genes that are a) predominantly expressed in the brain; b) specific for MAPK signaling; c) regulated by the dietary environment, and aim to unravel their impact on energy and glucose homeostasis.

Type 2 diabetes risk gene Dusp8

In 2009 and 2012, the MAP kinase phosphatase Dual-Specificity Phosphatase 8 (Dusp8) was first suggested as potential diabetes type 2 risk gene by large genome-wide association studies (GWAS). Dusp8 is predominantly expressed in the brain and, at least in vitro, specific for the c-Jun NH2-terminal kinase (Jnk), which is known to escalate the development of diabetes type 2 in obese individuals. Recently, we were able to reveal a sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance (Schriever et al. JCI 2020). This glucoregulatory role in mice was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. Overall, our findings suggested the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.

At current, in collaboration with the German Mouse Clinic we explore the role of Dusp8 in the control of behaviors such as anxiety and cognition, or sucrose reward.

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
(Source: Schriever SC et. al. Journal of Clinical Investigation 2020 Aug 11:136363. doi: 10.1172/JCI136363)