Maintenance of biological functions under negative energy balance depends on mobilization of storage lipids and carbohydrates in animals. In mammals, glucagon and glucocorticoid signaling mobilizes energy reserves, whereas adipokinetic hormones (AKHs) play a homologous role in insects. Numerous studies based on AKH injections and correlative studies in a broad range of insect species established the view that AKH acts as master regulator of energy mobilization during development, reproduction, and stress. In contrast to AKH, the second peptide, which is processed from the Akh encoded prohormone [termed “adipokinetic hormone precursor-related peptide” (APRP)] is functionally orphan. APRP is discussed as ecdysiotropic hormone or as scaffold peptide during AKH prohormone processing. However, as in the case of AKH, final evidence for APRP functions requires genetic mutant analysis. Here we employed CRISPR/Cas9-mediated genome engineering to create AKH and AKH plus APRP-specific mutants in the model insect Drosophila melanogaster. Lack of APRP did not affect any of the tested steroid-dependent processes. Similarly, Drosophila AKH signaling is dispensable for ontogenesis, locomotion, oogenesis, and homeostasis of lipid or carbohydrate storage until up to the end of metamorphosis. During adulthood, however, AKH regulates body fat content and the hemolymph sugar level as well as nutritional and oxidative stress responses. Finally, we provide evidence for a negative autoregulatory loop in Akh gene regulation.

https://www.genetics.org/content/genetics/201/2/665.full.pdf

Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants.

Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and FOXO3 being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.

/pdf/a-conserved-role-of-the-insulin-like-signaling-pathway-in-56k7coab92.pdf

A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster.

Metabolic homeostasis is regulated by the brain, but whether this regulation involves learning and memory of metabolic information remains unexplored. Here we use a calorie-based, taste-independent learning/memory paradigm to show that Drosophila form metabolic memories that help in balancing food choice with caloric intake; however, this metabolic learning or memory is lost under chronic high-calorie feeding. We show that loss of individual learning/memory-regulating genes causes a metabolic learning defect, leading to elevated trehalose and lipid levels. Importantly, this function of metabolic learning requires not only the mushroom body but also the hypothalamus-like pars intercerebralis, while NF-κB activation in the pars intercerebralis mimics chronic overnutrition in that it causes metabolic learning impairment and disorders. Finally, we evaluate this concept of metabolic learning/memory in mice, suggesting that the hypothalamus is involved in a form of nutritional learning and memory, which is critical for determining resistance or susceptibility to obesity. In conclusion, our data indicate that the brain, and potentially the hypothalamus, direct metabolic learning and the formation of memories, which contribute to the control of systemic metabolic homeostasis.

/pdf/metabolic-learning-and-memory-formation-by-the-brain-4bjfxecasc.pdf

Metabolic learning and memory formation by the brain influence systemic metabolic homeostasis

As the human lifespan has increased dramatically in recent decades, the amount of aging research has correspondingly increased. To investigate mechanisms of aging, an efficient model system is required. Although mammalian animal models are essential for aging studies, they are sometimes inappropriate due to their long lifespans and high maintenance costs. In this regard, insects can be effective alternative model systems for aging studies, as insects have a relatively short lifespan and cost less to maintain. Many species of insects have been used as model systems for aging studies, especially fruit flies, silkworm moths and several social insects. Fruit flies are most commonly used for aging studies due to the wide availability of abundant resources such as mutant stocks, databases and genetic tools. Silkworm moths are also good tools for studying aging at the tissue level due to their relatively large size. Last, social insects such as ants and bees are good for investigating lifespan determinants, as their lifespans significantly differ according to caste despite a constant genotype among the population. In this review, we discuss the current status and future prospects of aging research using insect model systems.

Insects as a model system for aging studies

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that predominantly affects people aged over 65 years. AD is marked by cognitive deficits and memory problems that worsen with age and ultimately results in death. Pathology of AD includes aggregation of the amyloid beta peptide into extracellular plaques and the presence of hyperphosphorylated tau in intracellular neurofibrillary tangles. Given that many factors are involved in the disease along with the ability to study individual aspects of disease pathology under controlled conditions, several genetically tractable animal models have been developed. Despite years of research, treatments remain limited and many therapies that yield promising data in animal models fail to translate it in humans. Here, we discuss the use of a highly versatile Drosophila melanogaster (aka fruit fly) model to study AD. The genetic machinery is conserved from fly to humans. The Drosophila eye has proved to be a genetically tractable model to study neurodegenerative disorders and for genetic and chemical screens. We highlight the utility of modeling AD by expressing human Aβ42 in the developing Drosophila retina. This system has been used recently to uncover new factors involved in the pathological activation of cell death pathways in AD. We discuss these findings and their role in the search for new disease treatments.

Unraveling Alzheimer’s Disease Using Drosophila

Drosophila is a genetically tractable system ideal for investigating the mechanisms of aging and developing interventions for promoting healthy aging. Here we describe methods commonly used in Drosophila aging research. These include basic approaches for preparation of diets and measurements of lifespan, food intake, and reproductive output. We also describe some commonly used assays to measure changes in physiological and behavioral functions of Drosophila in aging, such as stress resistance and locomotor activity.

/pdf/aging-studies-in-drosophila-melanogaster-18vsk6o1mb.pdf

Aging studies in Drosophila melanogaster.

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Aging studies in Drosophila melanogaster.