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A Mitochondrial Gene Product Regulates Metabolism

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A Mitochondrial Gene Product Regulates Metabolism NEWSFRONTS A mitochondrial gene product regulates metabolism Overconsumption of fat can lead to ­obesity and metabolic homeostasis. Lee and Cohen and to insulin resistance, a ­condition that first investigated how MOTS-c affects can also develop with age and often precedes ­metabolism in cell cultures and found that it diabetes. Investigators at the University stimulated glucose ­utilization. Next they eval- of Southern California (Los Angeles) uated whole-body m­ etabolism in adult mice. and University of California Los Angeles Treatment with MOTS-c for 4 days resulted recently reported that the effects of a high- in modest reductions in body weight, food fat diet could be ameliorated by treatment intake, blood ­glucose ­levels and biomarkers with a newly identified ­hormone encoded in of obesity and ­insulin ­resistance in the mice. an unexpected location: the m­ itochondria. Glucose t­olerance testing confirmed that Mitochondria are the key sources of c­ ellular ­treatment with MOTS-c for 7 days improved CamiloTorres/iStock/Thinkstock energy, so it might not seem surprising ­insulin ­sensitivity. Furthermore, MOTS-c in the mice. Overall, MOTS-c prevented that they are involved in metabolism, the ­administration for 7 days reversed age- obesity by increasing energy expenditure ­interconversion of en­ ergy and organic dependent insulin r­ esistance in treated mice. and ­improving glucose utilization and material. But most peptides are encoded Finally, the investigators examined the insulin sensitivity in mice fed a high-fat diet by nuclear DNA; this ­molecule is only the effects of MOTS-c on diet-induced obesity (Cell Metab. 21, 443–454; 2015). second peptide—and the first hormone— and insulin resistance in mice. Mice were On the basis of these results, the research found to be encoded by ­mitochondrial fed a high-fat diet in which 60% of total team suggests that MOTS-c or its deriva- DNA. “This discovery sheds new light on calories came from fat. Administration of tives might be ­useful in addressing the mitochondria and ­positions them as active MOTS-c for 8 weeks averted o­ besity in these abnormal metabolism associated with regulators of metabolism,” said Changhan mice without reducing total caloric intake aging in humans. As Cohen stated, “This Lee, who led the study together with Pinchas and also p­ revented h­ yperinsulinemia, represents a major advance in the identi- Cohen, in a press release. ­suggesting that it improved glucose fication of new treatments for age-related The mitochondrial hormone, referred ­homeostasis. Treatment with MOTS-c for diseases such as diabetes.” to as MOTS-c, regulates insulin sensitivity 3 weeks also increased body heat p­ roduction Monica Harrington UnDERStanDinG tHE linK bEtwEEn ObESitY anD inFERtilitY Overnutrition correlates with poor oocyte development in humans and produces distinct metabolic phenotypes in the offspring of rodent obesity models. On a cellular level, obesity and high levels of lipid exposure can induce a metabolic syndrome known as lipotoxicity, which impairs organelle functions and provokes cascading cellular stress responses. One particular response in the endoplasmic reticulum, known as ER stress, disrupts protein production and mitochondrial function to trigger various repair and survival mechanisms throughout the distressed cell. These disruptions, when they take place during oocyte development, can lead to later abnormalities during offspring development. Rebecca Robker (University of Adelaide, South Australia) and colleagues examined ovulation and offspring development in a rodent obesity model to assess whether ER stress contributes to obesity-related ovulatory dysfunctions (Development doi:10.1242/dev.114850; published online 15 February 2015). They used mice from a mutant strain called Blobby, which typically overeat and become obese when fed a standard diet. As expected, at obese weights Blobby mice showed impaired ovulation and produced fewer viable oocytes than wild-type mice. Furthermore, zygotes from obese Blobby mothers, after being fertilized in vitro and implanted in wild-type surrogates, developed into heavier fetuses than zygotes from wild-type mothers. Robker’s team used real-time reverse transcription PCR to confirm the presence of ER stress markers in cumulus-oocyte complexes of obese Blobby mothers and found reduced mitochondrial activity in ovulated oocytes after staining them with a mitochondrial membrane potential probe. They also found reduced amounts of mitochondrial DNA in blastocysts from obese Blobby mothers. These results suggest that ER stress during oocyte development affects the distribution of mitochondria throughout embryo development. This might explain why obese mothers produced offspring with greater adiposity. “The implication is that we’ve discovered a mechanism by which obesity can lead to altered metabolism in offspring,” Robker said in a press release. Working on this premise, Robker and her collaborators treated obese Blobby mothers with Salubrinal and BGP-15, both of which inhibit the ER stress response without affecting weight. These drugs restored oocyte viability, mitochondrial activity and normal embryonic development in obese Blobby mothers and their offspring. These outcomes underscore the critical effects of lipotoxicity and ER stress on fertility and embryonic development, identifying a mechanism by which maternal nutrition directly influences offspring metabolism. The drug BGP-15 is already being tested for human use as a potential treatment for type 2 diabetes, and the authors are now exploring its effects on isolated human eggs. Gregory D. Larsen 122 Volume 44, No. 4 | APRIL 2015 www.labanimal.com © 2015 Macmillan Publishers Limited. All rights reserved.
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