Absence of RIP140 Reveals a Pathway Regulating glut4-Dependent Glucose Uptake in Oxidative Skeletal Muscle through UCP1-Mediated Activation of AMPK

Abstract

Skeletal muscle constitutes the major site of glucose uptake leading to increased removal of glucose from the circulation in response to insulin. Type 2 diabetes and obesity are often associated with insulin resistance that can be counteracted by exercise or the use of drugs increasing the relative proportion of oxidative fibers. RIP140 is a transcriptional coregulator with a central role in metabolic tissues and we tested the effect of modulating its level of expression on muscle glucose and lipid metabolism in two mice models. Here, we show that although RIP140 protein is expressed at the same level in both oxidative and glycolytic muscles, it inhibits both fatty acid and glucose utilization in a fiber-type dependent manner. In RIP140-null mice, fatty acid utilization increases in the extensor digitorum longus and this is associated with elevated expression of genes implicated in fatty acid binding and transport. In the RIP140-null soleus, depletion of RIP140 leads to increased GLUT4 trafficking and glucose uptake with no change in Akt activity. AMPK phosphorylation/activity is inhibited in the soleus of RIP140 transgenic mice and increased in RIP140-null soleus. This is associated with increased UCP1 expression and mitochondrial uncoupling revealing the existence of a signaling pathway controlling insulin-independent glucose uptake in the soleus of RIP140-null mice. In conclusion, our findings reinforce the participation of RIP140 in the maintenance of energy homeostasis by acting as an inhibitor of energy production and particularly point to RIP140 as a promising therapeutic target in the treatment of insulin resistance.

Regulation of brown fat by AMP-activated protein kinase

“…of Pages 9 combustion of fat and a subsequent increase in energy status within the brown adipocytes. This conforms to a mechanism proposed by Fritah et al [74] in which increased mitochondrial uncoupling by UCP1 in muscle (in a model lacking a UCP1 transcriptional repressor) leads to an increased AMP/ATP ratio and subsequent AMPK activation. By contrast, b3-adrenergic stimulation increases AMPK phosphorylation in Ucp1 À/À adipocytes to the same extent as in WT adipocytes, indicating that AMPK activation is independent of the presence of UCP1 [54].…”

“…By contrast, b3-adrenergic stimulation increases AMPK phosphorylation in Ucp1 À/À adipocytes to the same extent as in WT adipocytes, indicating that AMPK activation is independent of the presence of UCP1 [54]. The consequential mechanism proposed by Fritah et al [74] is challenged by these data, emphasising that future research is necessary to provide clarity on whether AMPK activation is a cause or a consequence of uncoupling in BAT.…”

Neurolysin Knockout Mice Generation and Initial Phenotype Characterization

“…Several reports have shown that the skeletal muscle fiber composition is an important determinant in metabolism. Moreover, it is well established that slow twitch type I fibers act in glucose and lipid metabolism and endurance training promotes an increase of type I fiber muscles (67)(68)(69)(70)(71)(72). Indeed, the KO mice ran less than WT mice in the low intensity running regime until exhaustion.…”

Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches

“…The expression and promoter activity of CIDEA, an important regulatory factor in adipose cell function and obesity, is repressed by NRIP1 and induced by PGC-1α [100]. These genes are also involved in glucose uptake by affecting the regulation of both transcription and subcellular localization of the insulin-sensitive glucose transporter GLUT4 [101]. This evidence suggested that NRIP1 might be a potential therapeutic target in the treatment of insulin resistance in obese and type 2 diabetic patients [101].…”

“…These genes are also involved in glucose uptake by affecting the regulation of both transcription and subcellular localization of the insulin-sensitive glucose transporter GLUT4 [101]. This evidence suggested that NRIP1 might be a potential therapeutic target in the treatment of insulin resistance in obese and type 2 diabetic patients [101]. Accordingly, mice lacking Nrip1 are lean, show resistance to high-fat diet-induced obesity and have increased oxygen consumption [102].…”