A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila.

Sleep loss typically imposes negative effects on animal health. However, humans with a rare genetic mutation in the dec2 gene (dec2P384R) present an exception; these individuals sleep less without the usual effects associated with sleep deprivation. Thus, it has been suggested that the dec2P384R mutation activates compensatory mechanisms that allows these individuals to thrive with less sleep. To test this directly, we used a Drosophila model to study the effects of the dec2P384R mutation on animal health. Expression of human dec2P384R in fly sleep neurons was sufficient to mimic the short sleep phenotype and, remarkably, dec2P384R mutants lived significantly longer with improved health despite sleeping less. The improved physiological effects were enabled, in part, by enhanced mitochondrial fitness and upregulation of multiple stress response pathways. Moreover, we provide evidence that upregulation of pro-health pathways also contributes to the short sleep phenotype, and this phenomenon may extend to other pro-longevity models.

A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila.

Sleep loss typically imposes negative effects on animal health. However, humans with a rare genetic mutation in the dec2 gene ( dec2 P384R ) present an exception; these individuals sleep less without the usual effects associated with sleep deprivation. Thus, it has been suggested that the dec2 P384R mutation activates compensatory mechanisms that allows these individuals to thrive with less sleep. To test this directly, we used a Drosophila model to study the effects of the dec2 P384R mutation on animal health. Expression of human dec2 P384R in fly sleep neurons was sufficient to mimic the short sleep phenotype and, remarkably, dec2 P384R mutants lived significantly longer with improved health despite sleeping less. The improved physiological effects were enabled, in part, by enhanced mitochondrial fitness and upregulation of multiple stress response pathways. Moreover, we provide evidence that upregulation of pro-health pathways also contributes to the short sleep phenotype, and this phenomenon may extend to other pro-longevity models.

CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases.

Mutations in Valosin Containing Protein (VCP) are associated with several degenerative diseases, including multisystem proteinopathy (MSP-1) and amyotrophic lateral sclerosis. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. A deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. The power of a genetically tractable model organism coupled with well-established in vivo assays and a relatively short life cycle make Drosophila an attractive system to study VCP disease pathogenesis. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. Our models display many hallmarks of VCP-mediated degeneration, including progressive decline in mobility, protein aggregate accumulation and defects in lysosomal and mitochondrial function. We also made some novel and unexpected findings, including nuclear morphology defects and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models generated in this study will be useful for studying the etiology of individual VCP patient mutations and testing potential genetic and/or pharmacological therapies.

Examination of carnitine palmitoyltransferase 1 abundance in white adipose tissue: implications in obesity research.

Carnitine palmitoyltransferase 1 (CPT1) is essential for the transport of long-chain fatty acids into the mitochondria for oxidation. Recently, it was reported that decreased CPT1b mRNA in adipose tissue was a contributing factor for obesity in rats. We therefore closely examined the expression level of Cpt1 in adipose tissue from mice, rats, and humans. Cpt1a is the predominate isoform in adipose tissue from all three species. Rat white adipose tissue has a moderate amount of Cpt1b mRNA, but it is very minor compared with Cpt1b expression in muscle. Total CPT1 activity in adipose tissue is also minor relative to other tissues. Both Cpt1a and Cpt1b mRNA were increased in gonadal fat but not inguinal fat by diet-induced obesity in mice. We also measured CPT1a and CPT1b expression in subcutaneous adipose tissue from human subjects with a wide range of body mass indexes (BMIs). Interestingly, CPT1a expression positively correlated with BMI (R = 0.46), but there was no correlation with CPT1b (R = 0.04). Our findings indicate that white adipose tissue fatty acid oxidation capacity is minor compared with that of metabolically active tissues. Furthermore, given the already low abundance of Cpt1b in white adipose tissue, it is unlikely that decreases in its expression can quantitatively decrease whole body energy expenditure enough to contribute to an obese phenotype.

Impaired Mitochondrial Fat Oxidation Induces FGF21 in Muscle.

Fatty acids are the primary fuel source for skeletal muscle during most of our daily activities, and impaired fatty acid oxidation (FAO) is associated with insulin resistance. We have developed a mouse model of impaired FAO by deleting carnitine palmitoyltransferase-1b specifically in skeletal muscle (Cpt1b(m-/-)). Cpt1b(m-/-) mice have increased glucose utilization and are resistant to diet-induced obesity. Here, we show that inhibition of mitochondrial FAO induces FGF21 expression specifically in skeletal muscle. The induction of FGF21 in Cpt1b-deficient muscle is dependent on AMPK and Akt1 signaling but independent of the stress signaling pathways. FGF21 appears to act in a paracrine manner to increase glucose uptake under low insulin conditions, but it does not contribute to the resistance to diet-induced obesity.