Role of Hypothalamic Inflammation in Obesity?

Obesity has often been described as a state of “leptin resistance” – i.e. despite having elevated circulating levels of leptin, an adipocyte-derived “appetite inhibitor”, obese patients continue to consume calories in excess of their metabolic needs.

In this week’s issue of CELL, Xiaoqing Zhang and colleagues from the University of Wisconsin-Madison, demonstrate that obesity (or overnutrition) may activate inflammation pathways in the hypothalamus leading to central leptin resistance. This inflammation response is at least in part mediated by activation of the IKKβ/NF-κB pathway and the endoplasmic reticulum stress response, mechanisms that may also play a role in the peripheral inflammation often associated with obesity.

In their studies in mice, the researchers showed that while forced activation of hypothalamic IKKβ/NF-κB interrupts central insulin/leptin signaling and actions, site- or cell-specific suppression of IKKβ either broadly across the brain or locally within the hypothalamus actually protects against obesity and glucose intolerance.

These studies, at least in theory, point to a novel mechanism that can perhaps be pharmacologically manipulated to address leptin resistance and thereby “correct” the body’s ability to maintain energy homeostasis.

AMS
Phoenix, Arizona