Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response

Abstract

The brain, in particular the hypothalamus, plays a role in regulating glucose homeostasis; however, it remains unclear if the brain is causally involved in diabetic development. Here, we identified that hypothalamic TGF-β is excessive under conditions of not only obesity but aging, which are two general etiological factors of diabetes. Pharmacological and genetic approaches consistently revealed that brain TGF-β excess caused hyperglycemia and glucose intolerance in a body weight-independent manner. Cell-specific genetic models demonstrated that astrocytes are responsible for brain TGF-β excess, and POMC neurons are crucial for the pro-diabetic effect of TGF-β excess. Mechanistically, TGF-β excess induced hypothalamic RNA stress response to accelerate IκBα mRNA decay, leading to an atypical, mRNA metabolism-driven hypothalamic NF-κB activation which links obesity as well as aging to hypothalamic inflammation. In conclusion, brain TGF-β excess and induction of RNA stress response and hypothalamic inflammation are important for the pro-diabetic effects of obesity or aging.

Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion

“…Although i.t. infusion of TGF-β1 via a pump could be an option, direct systemic administration of TGF-β1 or its agonist may cause side effects such as diabetes (56). In contrast to the limited success of currently available drugs in treating devastating neuropathic pain, BMSCs offer distinct advantages for the efficacious treatment of chronic pain.…”

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…As a whole, this system is known as the proteostasis network (51). Both the consumption of large amounts of dietary fats and the process of aging can induce the expression of transforming growth factor-beta (TGFβ) by hypothalamic astrocytes (52). Upon its release from the astrocytes, TGFβ activates TGFβR2 in POMC neurons, inducing the formation of RNA stress granules that affect proteostasis by modifying the rate of translation of certain proteins (52).…”

“…Both the consumption of large amounts of dietary fats and the process of aging can induce the expression of transforming growth factor-beta (TGFβ) by hypothalamic astrocytes (52). Upon its release from the astrocytes, TGFβ activates TGFβR2 in POMC neurons, inducing the formation of RNA stress granules that affect proteostasis by modifying the rate of translation of certain proteins (52). In the case of obesity and aging, stress granules in POMC neurons induce the activation of nuclear factor kappa B (NFkB) signaling, leading to the dysfunction of POMC neuron activity.…”

“…In the case of obesity and aging, stress granules in POMC neurons induce the activation of nuclear factor kappa B (NFkB) signaling, leading to the dysfunction of POMC neuron activity. An important outcome of this process is that the hypothalamus can no longer exert appropriate control on hepatic gluconeogenesis (52). Thus, an early defect in a mechanism tightly connected to neuronal proteostasis can contribute to glucose intolerance through a connection between the hypothalamus and the liver (52,53).…”

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

“…Inhibition of IKKb/NF-kB signaling in the mediobasal hypothalamus, via viral overexpression of IkBa, inhibited endoplasmic reticulum stress-induced glucose intolerance as well as systemic and hepatic insulin resistance (20). A recent study suggests that the hypothalamic transforming growth factor-b, which is excessively produced under conditions of obesity, accompanied by hyperglycemia and glucose intolerance, leads to accelerated mRNA decay of IkBa (21). These data suggest that anti-inflammation approaches may be beneficial in treating the impaired glucose tolerance caused by overnutrition.…”