Loss of Angiotensin-converting enzyme-related (ACER) peptidase disrupts night-time sleep in adult Drosophila melanogaster

Abstract

SUMMARYDrosophila Acer (Angiotensin-converting enzyme-related) encodes a member of the angiotensin-converting enzyme family of metallopeptidases that have important roles in the endocrine regulation of blood homeostasis in mammals. Acer is expressed in the embryonic heart of Drosophila and expression in the adult head appears to be regulated by two clock genes. To study the role of Acer in development and in circadian activity, we have generated Acer null mutants by imprecise excision of a P-element and have compared their development and circadian behaviour with that of wild-type flies with the same genetic background. We show that Acer is not required for normal development, but that night sleep, which is clock regulated, is disrupted in adult flies lacking ACER. Acer null adults have reduced night-time sleep and greater sleep fragmentation, but normal levels of daytime sleep. The quality of night sleep in flies fed inhibitors of ACER is affected in a very similar manner. We have shown, using specific antibodies, that ACER is present in the adult fat body of the head and abdomen, and is secreted into the haemolymph. ACER might therefore have a role in cleaving regulatory peptides involved in metabolism and activity behaviour. There are similarities with mammals, where ACE peptidases are also expressed in adipose tissue and are thought to be part of a signalling system linking metabolism with sleep.

Genetic dissection of sleep–metabolism interactions in the fruit fly

“…Several sleep regulating genes are expressed preferentially in the fat body including Angiotensin-converting enzyme peptidase (ACER). Genetic mutation or pharmalogical blockade of ACER have disrupted nightime sleep, raising the possibility that the fat body functions to promote sleep (Carhan et al 2011). Fat body function appears to be particularly important for regulating homeostatic sleep changes in response to stressors including starvation and sleep-deprivation.…”

Factors that Differentially Affect Daytime and Nighttime Sleep in Drosophila melanogaster

“…Two independent null mutations of Acer , which affect neither the rhythm of locomotor activity nor the amount of daytime sleep, result in a twofold to threefold increase in the total locomotor activity during the night. As a result, nighttime sleep is reduced in these Acer mutants (Carhan et al, 2011). The longest sleep-bout during the night is shortened by approximately 50% in the mutants, resulting in fragmented nighttime sleep.…”

“…The longest sleep-bout during the night is shortened by approximately 50% in the mutants, resulting in fragmented nighttime sleep. These phenotypes are not due to simple hyperactivity, because the locomotor activity of Acer mutants during wakeful episodes is not greater than that in control flies (Carhan et al, 2011). The effect of the Acer mutations can be reproduced by pharmacological disruption of angiotensin-converting enzyme-related (ACER) activity with fosinopril, the ACE inhibitor used in the treatment of hypertension and chronic heart failure.…”

“…Drosophila Acer mRNA and protein are strongly expressed in the adult fat body (Carhan et al, 2011), which is physiologically analogous to liver and white adipose tissue in vertebrates, and is the organ primarily responsible for nutrient storage and metabolic control in Drosophila . Although the substrates of Drosophila ACER peptidase have not been identified, ACER may play a role similar to that of mammalian ACE in the processing of other peptide hormones, regulating energy, and metabolic homeostasis.…”

Necessity of angiotensin-converting enzyme-related gene for cardiac functions and longevity of Drosophila melanogaster assessed by optical coherence tomography

“…8 Other than its function in heart development, ACER also plays an important role in regulating sleeping behavior, as flies lacking ACER generally experience reduced nighttime sleep and exhibit greater sleep fragmentation. 10 As outlined above, the mammalian ACE2 regulates cardiac contractility mainly, whereas Drosophila ACER regulates heart development during embryogenesis. 8 Apart from this distinction, ACER also likely regulates the heart physiology in adult flies as it is expressed in the heart of Drosophila during development.…”