Leptin Resistance and Proteolytic Receptor Cleavage

Leptin receptors (red) in the hypothalamus at the third ventricle (3V) after a two-week control diet (CD) and high fat diet (HFD). The diet causes a loss of receptor density (arrows). For details see Mazor et al.

Loss of Satiety after Proteolytic Receptor Cleavage

Loss of Satiety and Desire to Eat During High Fat Diet is due to Proteolytic Cleavage of the Leptin Receptor in the Brain. It is an example for proteolytic receptor cleavage in the metabolic syndrome causing diverse co-morbidites.

Obesity is associated with increased blood concentrations of the hormone leptin; however, obese individuals are resistant to its effects.

We showed reduced leptin signaling in a high-fat diet-induced obesity model in mice. High fat diet promoted matrix metalloproteinase-2 (Mmp-2) activation in the hypothalamus, which cleaved the leptin receptor's extracellular domain and impaired leptin-mediated signaling. Deletion of Mmp-2 restored leptin receptor expression and reduced circulating leptin concentrations. In contrast, lentiviral delivery of Mmp-2 in the hypothalamus of Mmp-2-/- mice promoted leptin receptor cleavage and higher body weight. These results show a mechanism for leptin resistance through activation of Mmp-2 and subsequent cleavage of the extracellular domain of the leptin receptor in the hypothalamus.

Future Directions

  • Develop new therapeutic approaches to block MMP-2 activity in the brain of obese persons and at risk individuals.
  • Develop technology-assisted approaches to minimize calorie consumptions that can be adopted into one's regular lifestyle. A way to prevention.