In obesity, leptin resistance is the process by which the body no longer responds to leptin to inhibit energy intake and increase energy expenditure. The mechanisms that contribute to leptin resistance, however, remain unclear. Now, research has reported that a high-fat diet (HFD) in mice increases the concentration of metalloproteinase 2 (MMP2) in the hypothalamus and leptin receptor (ObR) signalling is impaired following the cleavage of the ObR extracellular domain by MMP2.
“The concept of leptin resistance is well established and patients with obesity are characterized by hyperleptinaemia and a diminished response to leptin,” explains co-corresponding author Dinorah Friedmann-Morvinski. “[We were intrigued by this as] in most cases of obesity, the [diminished response to leptin] is not associated with genetic defects in leptin or its receptors.”
In the present study, Friedmann-Morvinski, Rafi Mazor and colleagues investigated the mechanisms responsible for leptin resistance in obesity by inducing obesity in rats using a HFD and analysing total protease activity in brain lysates. The team found a global increase in the expression and activation of MMP2 in the brains of rats fed a HFD compared with the brains of rats fed a control diet. “Although the activity of MMP2 induced by HFD [was] not restricted to the hypothalamus, we focused our studies on this region as it affects food intake through the action of the leptin receptor,” write the authors.
Next, Friedmann-Morvinski and colleagues investigated the effect of incubation with MMP2 on the activity of ObR in hypothalamic cells. After treatment with MMP2, the expression of the ObR extracellular domain in the cells was reduced by >20%. The authors then used Mmp2-knockout mice to determine the effect of MMP2 depletion on HFD-induced obesity. The authors showed that MMP2-depleted mice had reduced weight gain when fed a HFD compared with wild-type littermates.
“[Following the Mmp2-knockout experiments], we needed a methodology that could show that depletion of MMP2 in the hypothalamus alone could result in reduced weight gain, which is why we adopted the lentiviral injections approach,” explains Friedmann-Morvinski. The team used lentiviral vectors to either knock down Mmp2 in the hypothalamus or to upregulate the expression of a mutant cleavage-resistant form of the ObR. Compared with control mice, mice lacking hypothalamic MMP2 that were fed a HFD gained less weight and had reduced plasma concentrations of leptin.
“I believe we have found a novel target and presented a possible new strategy to develop new treatment approaches to restore leptin sensitivity and hopefully decrease weight gain in people who are obese,” concludes Friedmann-Morvinski. “The challenge now is to find the way to deliver MMP2 inhibitors specifically to the hypothalamus.”
Mazor, R. et al. Cleavage of the leptin receptor by matrix metalloproteinase–2 promotes leptin resistance and obesity in mice. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aah6324 (2018)
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Morris, A. Mechanisms of leptin resistance revealed. Nat Rev Endocrinol 14, 628 (2018). https://doi.org/10.1038/s41574-018-0091-4