EarlyInflamHyp

The mediobasal hypothalamus (MBH) is a key brain area for multiple neuroendocrine and behavioral regulations. The MBH senses and integrates peripheral metabolic signals thanks to hypothalamic circumventricular organs composed of fenestrated median eminence (ME) vessels and local tanycytes that transport blood-derived molecules from the ME to the third ventricle reaching then the MBH cells. These highly coordinated communications between MBH and peripheral tissues are crucial for maintaining whole-body energy homeostasis. Disruption of this regulatory loop promotes several metabolic disorders including obesity and type 2 diabetes (T2D). Growing evidence considers chronic systemic inflammation induced by long-term overnutrition, such as high fat diet (HFD) feeding, as a preponderant mechanism for the development of obesity and T2D. Indeed, HFD feeding triggers an inflammatory response in the MBH, causing neuronal injuries and the impairment of MBH neurocircuits controlling energy balance, insulin sensitivity and glucose homeostasis ultimately leading to body weight gain, obesity and T2D. Remarkably, MBH inflammation and glucose intolerance occur rapidly upon short-term (ST) HFD consumption (within 1 to 3 days), long before the development of obesity, peripheral inflammation and metabolic disorders suggesting that MBH is the earliest brain region to be affected by ST-HFD that could initiate the pathogenesis of diet-induced obesity and insulin resistance. This suggests that ST-HFD generates endogenous signal (s) within the MBH to trigger or modulate acute hypothalamic inflammation and subsequent glucose intolerance. However, the mediators and the underlying mechanism, implicated in the onset of MBH neuroinflammation are still largely unknown. In this context, our pilot findings show that ST-HFD increases the expression of FGF21, a hepatokine recognized for its anti-inflammatory and insulin-sensitizing properties, in the MBH specifically in tanycytes and neurons. This upregulation parallels with MBH inflammation, glucose intolerance and increased expression of the nuclear receptor PPARa, known as a potent regulator of liver FGF21 expression, both in MBH neurons and tanycytes. Importantly, the knockdown of MBH FGF21 aggravates ST-HFD-induced hypothalamic inflammation and glucose intolerance, revealing MBH FGF21 as a critical component of the early regulation of these disorders. In addition, we have recently evidenced the hypothalamic expression of adiponectin, known as a downstream effector of FGF21. These data suggest the existence of new MBH signaling pathway, involving PPARa, FGF21 and adiponectin, which may be crucial in orchestrating the early onset of MBH inflammation. These findings also raise the question about the implication of this pathway in long-term HFD-induced obesity and metabolic dysfunctions. Thus, The EarlyInflamHyp proposal aims to : (1) unravel whether tanycytic or neuronal FGF21 may regulate ST-HFD induced MBH inflammation and glucose intolerance; (2) explore the contribution of MBH-produced FGF21 on neuronal adiponectin production to counteract ST-HFD effects on MBH inflammation and systemic glucose intolerance; (3) decipher the molecular mechanisms by which ST-HFD increases FGF21 expression in MBH tanycytes and neurons, and to determine the implication of PPARa; (4) investigate the implication of the PPARa/FGF21/adiponectin signaling pathway in long-term HFD-induced hypothalamic inflammation and related metabolic disorders. EarlyInflamHyp proposa will bring breakthroughs in the comprehension of the cellular and molecular mechanisms linking acute HFD-induced hypothalamic neuroinflammation to the development/progression of obesity and its related metabolic disorders i.e., glucose intolerance and insulin resistance. our proposal will also pave the way towards the identification of promising therapeutic targets for an early intervention to prevent HFD-induced hypothalamic inflammation and related diseases.