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Overconsumption of fat can lead to obesity and to insulin resistance, a condition that can also develop with age and often precedes diabetes. Investigators at the University of Southern California (Los Angeles) and University of California Los Angeles recently reported that the effects of a highfat diet could be ameliorated by treatment with a newly identified hormone encoded in an unexpected location: the m itochondria. Mitochondria are the key sources of c ellular energy, so it might not seem surprising that they are involved in metabolism, the i nterconversion of e nergy and organic material. But most peptides are encoded by nuclear DNA; this molecule is only the second peptide—and the first hormone— found to be encoded by m itochondrial DNA. “This discovery sheds new light on mitochondria and positions them as active regulators of metabolism,” said Changhan Lee, who led the study together with Pinchas Cohen, in a press release. The mitochondrial hormone, referred to as MOTS-c, regulates insulin sensitivity
and metabolic homeostasis. Lee and Cohen first investigated how MOTS-c affects metabolism in cell cultures and found that it stimulated glucose utilization. Next they evaluated whole-body m etabolism in adult mice. Treatment with MOTS-c for 4 days resulted in modest reductions in body weight, food intake, blood glucose l evels and biomarkers of obesity and insulin resistance in the mice. Glucose t olerance testing confirmed that treatment with MOTS-c for 7 days improved insulin sensitivity. Furthermore, MOTS-c administration for 7 days reversed agedependent insulin r esistance in treated mice. Finally, the investigators examined the effects of MOTS-c on diet-induced obesity and insulin resistance in mice. Mice were fed a high-fat diet in which 60% of total calories came from fat. Administration of MOTS-c for 8 weeks averted o besity in these mice without reducing total caloric intake and also p revented h yperinsulinemia, s uggesting that it improved glucose homeostasis. Treatment with MOTS-c for 3 weeks also increased body heat p roduction
CamiloTorres/iStock/Thinkstock
A mitochondrial gene product regulates metabolism
in the mice. Overall, MOTS-c prevented obesity by increasing energy expenditure and i mproving glucose utilization and insulin sensitivity in mice fed a high-fat diet (Cell Metab. 21, 443–454; 2015). On the basis of these results, the research team suggests that MOTS-c or its derivatives might be u seful in addressing the abnormal metabolism associated with aging in humans. As Cohen stated, “This represents a major advance in the identification of new treatments for age-related diseases such as diabetes.” 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
Overconsumption of fat can lead to obesity and to insulin resistance, a condition that can also develop with age and often precedes diabetes. Investigators at the University of Southern California (Los Angeles) and University of California Los Angeles recently reported that the effects of a highfat diet could be ameliorated by treatment with a newly identified hormone encoded in an unexpected location: the m itochondria. Mitochondria are the key sources of c ellular energy, so it might not seem surprising that they are involved in metabolism, the i nterconversion of e nergy and organic material. But most peptides are encoded by nuclear DNA; this molecule is only the second peptide—and the first hormone— found to be encoded by m itochondrial DNA. “This discovery sheds new light on mitochondria and positions them as active regulators of metabolism,” said Changhan Lee, who led the study together with Pinchas Cohen, in a press release. The mitochondrial hormone, referred to as MOTS-c, regulates insulin sensitivity
and metabolic homeostasis. Lee and Cohen first investigated how MOTS-c affects metabolism in cell cultures and found that it stimulated glucose utilization. Next they evaluated whole-body m etabolism in adult mice. Treatment with MOTS-c for 4 days resulted in modest reductions in body weight, food intake, blood glucose l evels and biomarkers of obesity and insulin resistance in the mice. Glucose t olerance testing confirmed that treatment with MOTS-c for 7 days improved insulin sensitivity. Furthermore, MOTS-c administration for 7 days reversed agedependent insulin r esistance in treated mice. Finally, the investigators examined the effects of MOTS-c on diet-induced obesity and insulin resistance in mice. Mice were fed a high-fat diet in which 60% of total calories came from fat. Administration of MOTS-c for 8 weeks averted o besity in these mice without reducing total caloric intake and also p revented h yperinsulinemia, s uggesting that it improved glucose homeostasis. Treatment with MOTS-c for 3 weeks also increased body heat p roduction
CamiloTorres/iStock/Thinkstock
A mitochondrial gene product regulates metabolism
in the mice. Overall, MOTS-c prevented obesity by increasing energy expenditure and i mproving glucose utilization and insulin sensitivity in mice fed a high-fat diet (Cell Metab. 21, 443–454; 2015). On the basis of these results, the research team suggests that MOTS-c or its derivatives might be u seful in addressing the abnormal metabolism associated with aging in humans. As Cohen stated, “This represents a major advance in the identification of new treatments for age-related diseases such as diabetes.” 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
