I read with great interest the recent study by Valdearcos et al titled “Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility” and published in the journal of Cell Metabolism. The authors neatly demonstrate that hypothalamic microglia rapidly increase in response to high fat diet in a mouse model. Increased microglia result in increased inflammation in the hypothalamus and neuronal stress. This is turn leads to reduced sensitivity to homeostatic signals like leptin leading to over-consumption and weight gain. This study represents the first evidence linking dietary over-consumption and hypothalamic dysfunction leading to fat accumulation. Center to hypothalamic dysfunction is increased inflammation caused by increased microglia. Microglia are macrophage cells and are the first and main immune defense in the brain. They typically respond to infections but in the case of obesity they respond to excess dietary fat.

It is quite refreshing to read such studies that demonstrate the role of the hypothalamus in energy metabolism and obesity. The hypothalamus regulates body weight the same it controls body temperature. Unless the set point for body weight is altered weight gain, or loss cannot occur. Increased inflammation mediated by the immune system in response to increased fat consumption seems to alter the hypothalamic set point for body weight. Excessive food consumption or consumption of certain types of nutrients like saturated fats causes immune system over-activation. This in turn leads to chronic inflammation. Valdearcos et al nicely show that chronic inflammation in the hypothalamus reduces its ability to respond to leptin leading to obesity. Hundreds of neuro-hormonal signals convey messages to the hypothalamus from peripheral organs like the gastro-intestinal tract, pancreas, liver and adipose tissue. The hypothalamus integrates these messages to maintain a stable body weight. It would be interesting to study the effect of sleeve gastrectomy and gastric bypass surgery on hypothalamic inflammation. Weight loss surgery resets the hypothalamic set point for body weight. Does weight loss surgery decrease hypothalamic microglia and associated inflammation? We know that GLP-1 and PYY increase after weight loss surgery. It is possible for such an increase to overcome the hypothalamic resistance to respond to such signals. With decreased calorie intake and increased hypothalamic response to gut signals, weight loss surgery achieves durable and significant weight loss. Calorie restriction by itself, without restoring the hypothalamic set point of body weight, is not likely to resolve the underlying pathophysiology of obesity.