Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

Abstract

Recent genome-wide association studies (GWAS) identified DUSP8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes (T2D) risk gene. Here, we unravel Dusp8 as gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male but not female Dusp8 loss-of-function mice, either with global or CRH neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal (HPA) axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8 KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity and systemic glucose tolerance was consistent with fMRI 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. In summary, our findings suggest the GWAS-identified gene Dusp8 as novel hypothalamic factor that plays a functional role in the etiology of T2D.

Diabetes type 2 risk gene Dusp8 is associated with altered sucrose reward behavior in mice and humans

“…Based on the close proximity of SNP rs2334499 to the gene dual specificity phosphatase 8 (DUSP8), a likely relationship had been implicated (Kong et al., 2009; Morris et al., 2012). Consistent with that still unexplored assumption, we found hypothalamic insulin resistance and systemic glucose intolerance in high‐fat diet‐fed Dusp8 KO mice (Schriever et al., 2020). Mechanistically, we revealed an impaired HPA axis feedback control with chronic hypercorticosteronemia, and an altered sympathetic nervous system tone as driving factors for the dysfunctional glucose control in Dusp8 KO mice.…”

“…Recently, we revealed hypothalamic insulin resistance in human carriers of the minor T/T allele of SNP rs2334499 (Schriever et al., 2020), a frequent polymorphism previously associated with a modestly increased T2D risk (Kong et al., 2009; Morris et al., 2012). Based on the close proximity of SNP rs2334499 to the gene dual specificity phosphatase 8 (DUSP8), a likely relationship had been implicated (Kong et al., 2009; Morris et al., 2012).…”

“…Dusp8 is a phosphatase specific for mitogen‐activated kinases (MAPK) that is predominantly expressed in the brain and to lesser extent in muscles and bone (Martell et al., 1995; Schriever et al., 2020). The specificity of Dusp8 toward MAPK appears to be tissue and context dependent.…”

“…The specificity of Dusp8 toward MAPK appears to be tissue and context dependent. Dusp8 overexpressed in cells showed highest dephosphorylation activities toward Jnk and minor activities toward p38, and an absence of activity toward Erk (Muda et al., 1996; Schriever et al., 2020). In vivo, global Dusp8 deficient mice had Jnk hyperactivation in the hypothalamus (Schriever et al., 2020), but Erk hyperactivation in the hippocampus (Baumann et al., 2019) and the heart (Liu et al., 2016).…”

“…Dusp8 overexpressed in cells showed highest dephosphorylation activities toward Jnk and minor activities toward p38, and an absence of activity toward Erk (Muda et al., 1996; Schriever et al., 2020). In vivo, global Dusp8 deficient mice had Jnk hyperactivation in the hypothalamus (Schriever et al., 2020), but Erk hyperactivation in the hippocampus (Baumann et al., 2019) and the heart (Liu et al., 2016). These data are consistent with a complex crosstalk of MAPK that is finely regulated by numerous scaffold proteins and Dusp family members (Farooq & Zhou, 2004); they further suggest a prominent and tissue‐specific role for Dusp8 in MAPK signaling and function.…”