Mitogen-Activated Protein Kinase Phosphatase 3 (MKP-3)–Deficient Mice Are Resistant to Diet-Induced Obesity

Abstract

Mitogen-activated protein kinase phosphatase 3 (MKP-3) is a negative regulator of extracellular signal–related kinase signaling. Our laboratory recently demonstrated that MKP-3 plays an important role in obesity-related hyperglycemia by promoting hepatic glucose output. This study shows that MKP-3 deficiency attenuates body weight gain induced by a high-fat diet (HFD) and protects mice from developing obesity-related hepatosteatosis. Triglyceride (TG) contents are dramatically decreased in the liver of MKP-3−/− mice fed an HFD compared with wild-type (WT) controls. The absence of MKP-3 also reduces adiposity, possibly by repressing adipocyte differentiation. In addition, MKP-3−/− mice display increased energy expenditure, enhanced peripheral glucose disposal, and improved systemic insulin sensitivity. We performed global phosphoproteomic studies to search for downstream mediators of MKP-3 action in liver lipid metabolism. Our results revealed that MKP-3 deficiency increases the phosphorylation of histone deacetylase (HDAC) 1 on serine 393 by 3.3-fold and HDAC2 on serine 394 by 2.33-fold. Activities of HDAC1 and 2 are increased in the livers of MKP-3−/− mice fed an HFD. Reduction of HDAC1/2 activities is sufficient to restore TG content of MKP-3−/− primary hepatocytes to a level similar to that in WT cells.

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…MKP-3 inhibition is capable of facilitating energy expenditure, peripheral glucose disposal, and insulin signaling in association with phosphorylation of HDAC 1 on serine 393 and HDAC2 on serine 394. HDAC1/2 is increased in livers of MKP-3 knockout mice fed a high fat diet to mediate the MKP-3 inhibition-offered metabolic benefits (Feng et al, 2014). These observations are in line with the downregulated transcript levels of HDAC2 and cardiac α-actin in murine hearts following a two-week Western diet feeding.…”

Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism

“…Consistent with this, high-fat diet fed MKP-3-deficient mice exhibited fasting blood glucose and fasting plasma insulin concentrations that were significantly lower in MKP-3 knockout mice compared with wild-type mice [53]. The livers of MKP-3 deficient mice were also protected from the development of hepatosteatosis [53]. These studies are provocative as they suggest a potential role for a non-MAPK substrate for MKP-3 in metabolism.…”

“…This raises the possibility that MKP-3 indirectly regulates FOXO1 via ERK1/2 in the control of hepatic gluconeogenesis. In subsequent studies using a diet-induced obesity model, Feng et al utilized MKP-3-deficient mice and showed that these mice were resistant to diet-induced obesity [53]. Consistent with this, high-fat diet fed MKP-3-deficient mice exhibited fasting blood glucose and fasting plasma insulin concentrations that were significantly lower in MKP-3 knockout mice compared with wild-type mice [53].…”

“…In subsequent studies using a diet-induced obesity model, Feng et al utilized MKP-3-deficient mice and showed that these mice were resistant to diet-induced obesity [53]. Consistent with this, high-fat diet fed MKP-3-deficient mice exhibited fasting blood glucose and fasting plasma insulin concentrations that were significantly lower in MKP-3 knockout mice compared with wild-type mice [53]. The livers of MKP-3 deficient mice were also protected from the development of hepatosteatosis [53].…”

Measurement of Resting Energy Metabolism in Mice Using Oxymax Open Circuit Indirect Calorimeter

“…From the measurement of VO 2 and VCO 2 , the respiratory exchange ratio (RER) can be calculated to assess energy fuel utilization and energy expenditure (Evan et al , 2012). Previously, indirect calorimeter has been widely used in metabolic disease research in mice to reveal the potential roles of specific genes or treatments in regulating energy metabolism (for example: Bi et al , 2014; Feng et al , 2014). Here, we described a protocol to evaluate the resting energy metabolism of C57BL/6 mice during dark and light cycles using the Oxymax Open Circuit indirect calorimeter.…”