Cleavage of the leptin receptor by matrix metalloproteinase–2 promotes leptin resistance and obesity in mice

Abstract

Obesity and related morbidities pose a major health threat. Obesity is associated with increased blood concentrations of the anorexigenic hormone leptin; however, obese individuals are resistant to its anorexigenic effects. We examined the phenomenon of reduced leptin signaling in a high-fat diet-induced obesity model in mice. Obesity 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 obese mice. Lentiviral delivery of short hairpin RNA to silence in the hypothalamus of wild-type mice prevented leptin receptor cleavage and reduced fat accumulation. In contrast, lentiviral delivery of in the hypothalamus of mice promoted leptin receptor cleavage and higher body weight. In a genetic mouse model of obesity, transduction of cleavage-resistant leptin receptor in the hypothalamus reduced the rate of weight gain compared to uninfected mice or mice infected with the wild-type receptor. Immunofluorescence analysis showed that astrocytes and agouti-related peptide neurons were responsible for Mmp-2 secretion in mice fed a high-fat diet. These results suggest a mechanism for leptin resistance through activation of Mmp-2 and subsequent cleavage of the extracellular domain of the leptin receptor.

Vesicles Shed by Pathological Murine Adipocytes Spread Pathology: Characterization and Functional Role of Insulin Resistant/Hypertrophied Adiposomes

“…This is the situation for 72kDa type IV collagenase (MMP-2), fatty acid-binding protein 4 (FABP-4), and transforming growth factor beta induced protein ig-h3 (TFGBI) that were elevated in EVs from insulin resistant adipocytes by HGHI. MMP-2 was described as elevated at circulating level in obese humans [20], and furthermore, it has been implicated in leptin resistance causing IR and obesity in mice by leptin receptor cleavage [50]. Additionally, the adipocyte protein FABP4 has been previously associated to obesity and metabolic syndrome [25].…”

High-fat diet enhances starvation-induced hyperactivity via sensitizing hunger-sensing neurons in Drosophila

“…Several lines of evidence have begun to reveal the underlying neural mechanisms. For example, HFD increases the intrinsic excitability of orexigenic NPY/AgRP neurons (Vernia et al, 2016), induces leptin resistance (Mazor et al, 2018;Olofsson et al, 2013), and enhances their inhibitory innervations with anorexigenic POMC neurons (Newton et al, 2013), altogether resulting in hypersensitivity to starvation and increased food consumption. Interestingly, besides HFD, other metabolic challenges, including maternal HFD, alcohol consumption, as well as aging, also disrupt normal food intake via affecting the excitability and/or innervation of NPY/AgRP neurons (Cains et al, 2017;Furedi et al, 2018;Rivera et al, 2015).…”

Leptin resensitisation: a reversion of leptin-resistant states

“…Recently, matrix metalloproteinase-2 (Mmp-2) has been suggested as a key mediator of leptin resistance. Obesity promotes the hypothalamic Mmp-2 activity and its secretion from the astrocytes and AgRP neurons (Mazor et al 2018). Mmp-2 cleaves the extracellular domain of LepRb and diminishes leptin action (Mazor et al 2018).…”