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

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a 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 corticotropin-releasing hormone 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 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 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. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.

Alterations in neuronal control of body weight and anxiety behavior by glutathione peroxidase 4 deficiency.

Elevated levels of oxidative stress and neuronal inflammation in the hypothalamus or ventral midbrain, respectively, represent common denominators for obesity and Parkinson's Disease (PD). However, little is known about defense mechanisms that protect neurons in these regions from oxidative damage. Here, we aimed to assess whether murine Gpx4, a crucial antioxidant enzyme that protects neurons from membrane damage and ferroptosis, is critical for the protection from neuronal inflammation in two distinct pathophysiologic diseases, namely metabolic dysfunction in diet-induced obesity or PD. Gpx4 was deleted from either AgRP or POMC neurons in the hypothalamus, essential for metabolic homeostasis, or from dopaminergic neurons in the ventral midbrain, governing behaviors such as anxiety or voluntary movement. To induce a pro-inflammatory environment, AgRP and POMC neuron-specific Gpx4 knockout mice were subjected to high-fat high-sucrose (HFHS) diet. To exacerbate oxidative stress in dopaminergic neurons of the ventral midbrain, we systemically co-deleted the PD-related gene DJ-1. Gpx4 was dispensable for the maintenance of cellular health and function of POMC neurons, even in mice exposed to obesogenic conditions. In contrast, HFHS-fed mice with Gpx4 deletion from AgRP neurons displayed increased body adiposity. Gpx4 expression and activity were diminished in the hypothalamus of HFHS-fed mice compared to standard diet-fed controls. Gpx4 deletion from dopaminergic neurons induced anxiety behavior, and diminished spontaneous locomotor activity when DJ-1 was co-deleted. Overall, these data suggest a physiological role for Gpx4 in balancing metabolic control signals and inflammation in AgRP but not POMC neurons. Moreover, Gpx4 appears to constitute an important rheostat against neuronal dysfunction and PD-like symptoms in dopaminergic circuitry within the ventral midbrain.