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Cancer cachexia is a systemic metabolic dysfunction that affects more than 80% of pancreatic cancer patients and is the leading cause of death in 22%–30% of all cancers. Because the cancer spread beyond the pancreas at the time of diagnosis, only about 20% of patients are candidates for surgery. Pancreatic cancer's aggressiveness destabilizes whole-body homeostasis by dismantling the normal network of organs crosstalk. This miss-communication favors the tumor progression during cancer cachexia, which is characterized by devastating body weight lossmuscle atrophy, fat wasting, decreased appetite. The molecular mechanisms underlying these metabolic cues are still being investigated.

Mengistu Lemecha, Jaya Prakash Chalise, Yuki Takamuku, Guoxiang Zhang, ... Keiichi Itakura

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Current Issue

Declining muscle NAD+ in a hyperandrogenism PCOS mouse model: Possible role in metabolic dysregulation

Ali Aflatounian, Valentina Rodriguez Paris, Dulama Richani, Melissa C. Edwards, ... Kirsty A. Walters

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, defined by reproductive and endocrine abnormalities, with metabolic dysregulation including obesity, insulin resistance and hepatic steatosis. Recently, it was found that skeletal muscle insulin sensitivity could be improved in obese, post-menopausal, pre-diabetic women through treatment with nicotinamide mononucleotide (NMN), a precursor to the prominent redox cofactornicotinamide adenine dinucleotide (NAD+). Given that PCOS patients have a similar endocrine profile to these patients, we hypothesised that declining NAD levels in muscle might play a role in the pathogenesis of the metabolic syndrome associated with PCOS, and that this could be normalized through NMN treatment. Here, we tested the impact of NMN treatment on the metabolic syndrome of the dihydrotestosterone (DHT) induced mouse model of PCOS. We observed lower NAD levels in the muscle of PCOS mice, which was normalized by NMN treatment. PCOS mice were hyperinsulinaemic, resulting in increased adiposity and hepatic lipid deposition. Strikingly, NMN treatment completely normalized these aspects of metabolic dysfunction. We propose that addressing the decline in skeletal muscle NAD levels associated with PCOS can normalize insulin sensitivity, preventing compensatory hyperinsulinaemia, which drives obesity and hepatic lipid deposition, though we cannot discount an impact of NMN on other tissues to mediate these effects. These findings support further investigation into NMN treatment as a new therapy for normalizing the aberrant metabolic features of PCOS.

Declining muscle NAD+ in a hyperandrogenism PCOS mouse model: Possible role in metabolic dysregulation

Ali Aflatounian, Valentina Rodriguez Paris, Dulama Richani, Melissa C. Edwards, ... Kirsty A. Walters

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, defined by reproductive and endocrine abnormalities, with metabolic dysregulation including obesity, insulin resistance and hepatic steatosis. Recently, it was found that skeletal muscle insulin sensitivity could be improved in obese, post-menopausal, pre-diabetic women through treatment with nicotinamide mononucleotide (NMN), a precursor to the prominent redox cofactornicotinamide adenine dinucleotide (NAD+). Given that PCOS patients have a similar endocrine profile to these patients, we hypothesised that declining NAD levels in muscle might play a role in the pathogenesis of the metabolic syndrome associated with PCOS, and that this could be normalized through NMN treatment. Here, we tested the impact of NMN treatment on the metabolic syndrome of the dihydrotestosterone (DHT) induced mouse model of PCOS. We observed lower NAD levels in the muscle of PCOS mice, which was normalized by NMN treatment. PCOS mice were hyperinsulinaemic, resulting in increased adiposity and hepatic lipid deposition. Strikingly, NMN treatment completely normalized these aspects of metabolic dysfunction. We propose that addressing the decline in skeletal muscle NAD levels associated with PCOS can normalize insulin sensitivity, preventing compensatory hyperinsulinaemia, which drives obesity and hepatic lipid deposition, though we cannot discount an impact of NMN on other tissues to mediate these effects. These findings support further investigation into NMN treatment as a new therapy for normalizing the aberrant metabolic features of PCOS.

2021 impact factor: 8.568

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