Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Abstract

Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.fatty acid oxidation | adipocytes | mitochondrial CO 2 production

Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling

“…In addition, we also checked the expression of two known miR-378/378* targets, carnitine O-acetyltransferase (Crat) and mediator complex subunit 13 (Med13). Consistent with the previously reported result 21 , the expression levels of both Crat and Med13 in the liver of 378KO mice on normal chow were not altered ( Supplementary Fig. 6j).…”

“…In breast cancer, miR-378* upregulation results in an increase in cell proliferation and lactate production, and a repression of tricarboxylic acid cycle and oxygen consumption, indicating that miR-378* is able to mediate metabolic shift in cancer cells 20 . It has also been reported that hepatic miR-378/378* expression is dysregulated in a rat model of type 2 diabetes and obese mouse models, including genetic ob/ob mice and mice fed a high-fat diet 15,21,22 . However, whether and how miR-378 or miR-378* plays a regulatory role in hepatic glucose and lipid metabolism remains unclear.…”

“…Mice genetically lacking miR-378/378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism, suggesting that miR-378/ 378* might be involved in the regulation of mitochondrial metabolism and systemic energy homeostasis 21 . In breast cancer, miR-378* upregulation results in an increase in cell proliferation and lactate production, and a repression of tricarboxylic acid cycle and oxygen consumption, indicating that miR-378* is able to mediate metabolic shift in cancer cells 20 .…”

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

“…Among these varied biological responses, a common mechanism of action appears to be the promotion of oxidative metabolism accompanying the stimulation of mitochondria biogenesis. The promotion of fatty acid oxidative metabolism leads to a reduction of fat accumulation in muscle, which, in turn, increases insulin sensitivity and the glucose uptake by insulin-sensitive tissues [64].PGC1-β is encoded by the Ppargc1b gene and is preferentially expressed in tissues with relatively high mitochondrial content, including heart, slow skeletal muscle and BAT [3]. PGC1-β knockout mice display an altered expression in a large number of nuclear-encoded genes that regulate mitochondria energy metabolism in multiple tissues and these mice are extremely sensitive to cold exposure and develop hepatic steatosis upon feeding with high fat diet [69,73].…”

“…In fact, the number of overweight and obese people rose from 857 million in 1980 to 2.1 billion in 2013 [2]. Recently, obesity and metabolic syndrome were associated with mitochondrial dysfunction and deranged regulation of metabolic genes [3]. Interestingly, mitochondria of obese individuals seem to be different from those of lean individuals.…”