LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.

Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity.

A gut-derived hormone suppresses sugar appetite and regulates food choice in Drosophila.

Animals must adapt their dietary choices to meet their nutritional needs. How these needs are detected and translated into nutrient-specific appetites that drive food-choice behaviours is poorly understood. Here we show that enteroendocrine cells of the adult female Drosophila midgut sense nutrients and in response release neuropeptide F (NPF), which is an ortholog of mammalian neuropeptide Y-family gut-brain hormones.

Insulin signaling couples growth and early maturation to cholesterol intake in Drosophila.

Nutrition is one of the most important influences on growth and the timing of maturational transitions including mammalian puberty and insect metamorphosis. Childhood obesity is associated with precocious puberty, but the assessment mechanism that links body fat to early maturation is unknown. During development, the intake of nutrients promotes signaling through insulin-like systems that govern the growth of cells and tissues and also regulates the timely production of the steroid hormones that initiate the juvenile-adult transition.

The gut hormone Allatostatin C/Somatostatin regulates food intake and metabolic homeostasis under nutrient stress.

The intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal information to other organs to coordinate systemic energy balance. However, the gut-derived hormones affecting metabolic and behavioral responses are poorly defined.

A nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila.

Animals maintain metabolic homeostasis by modulating the activity of specialized organs that adjust internal metabolism to external conditions. However, the hormonal signals coordinating these functions are incompletely characterized. Here we show that six neurosecretory cells in the Drosophila central nervous system respond to circulating nutrient levels by releasing Capa hormones, homologs of mammalian neuromedin U, which activate the Capa receptor (CapaR) in peripheral tissues to control energy homeostasis.

Interorgan communication in the control of metamorphosis.

Steroid hormones control major developmental transitions such as metamorphosis in insects and puberty in mammals. The juvenile must attain a sufficient size before it begins maturation in order to give rise to a properly sized and reproductively fit adult. Studies in the insect Drosophila have begun to reveal a remarkable example of the complex interplay between different organs and the neuroendocrine system that controls the production of the steroid ecdysone, which triggers metamorphosis.

Regulation of Body Size and Growth Control.

The control of body and organ growth is essential for the development of adults with proper size and proportions, which is important for survival and reproduction. In animals, adult body size is determined by the rate and duration of juvenile growth, which are influenced by the environment. In nutrient-scarce environments in which more time is needed for growth, the juvenile growth period can be extended by delaying maturation, whereas juvenile development is rapidly completed in nutrient-rich conditions.

Ecdysone-dependent feedback regulation of prothoracicotropic hormone controls the timing of developmental maturation.

The activation of a neuroendocrine system that induces a surge in steroid production is a conserved initiator of the juvenile-to-adult transition in many animals. The trigger for maturation is the secretion of brain-derived neuropeptides, yet the mechanisms controlling the timely onset of this event remain ill-defined. Here, we show that a regulatory feedback circuit controlling the neuropeptide Prothoracicotropic hormone (PTTH) triggers maturation onset.

Metabolism and growth adaptation to environmental conditions in Drosophila.

Organisms adapt to changing environments by adjusting their development, metabolism, and behavior to improve their chances of survival and reproduction. To achieve such flexibility, organisms must be able to sense and respond to changes in external environmental conditions and their internal state. Metabolic adaptation in response to altered nutrient availability is key to maintaining energy homeostasis and sustaining developmental growth.

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control.

The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known genes, the contribution of each of these to the 22q11.

Autophagy regulates steroid production by mediating cholesterol trafficking in endocrine cells.

Steroid hormones are made from cholesterol and are essential for many developmental processes and disease conditions. The production of these hormones is nutrient dependent and tightly controlled by mechanisms that involve delivery of the precursor molecule cholesterol stored in lipid droplets (LDs). Recent studies have implicated macroautophagy/autophagy, a process regulated by nutrition, in the degradation of LDs and the mobilization of stored lipids.

A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion.

Organisms adapt their metabolism and growth to the availability of nutrients and oxygen, which are essential for development, yet the mechanisms by which this adaptation occurs are not fully understood. Here we describe an RNAi-based body-size screen in Drosophila to identify such mechanisms. Among the strongest hits is the fibroblast growth factor receptor homolog breathless necessary for proper development of the tracheal airway system.

Autophagy-Mediated Cholesterol Trafficking Controls Steroid Production.

Steroid hormones are important signaling molecules that regulate growth and drive the development of many cancers. These factors act as long-range signals that systemically regulate the growth of the entire organism, whereas the Hippo/Warts tumor-suppressor pathway acts locally to limit organ growth. We show here that autophagy, a pathway that mediates the degradation of cellular components, also controls steroid production.

AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance.

The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the β-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell.

Modulation of Drosophila post-feeding physiology and behavior by the neuropeptide leucokinin.

Behavior and physiology are orchestrated by neuropeptides acting as central neuromodulators and circulating hormones. An outstanding question is how these neuropeptides function to coordinate complex and competing behaviors. In Drosophila, the neuropeptide leucokinin (LK) modulates diverse functions, but mechanisms underlying these complex interactions remain poorly understood.

Warts Signaling Controls Organ and Body Growth through Regulation of Ecdysone.

Coordination of growth between individual organs and the whole body is essential during development to produce adults with appropriate size and proportions [1, 2]. How local organ-intrinsic signals and nutrient-dependent systemic factors are integrated to generate correctly proportioned organisms under different environmental conditions is poorly understood. In Drosophila, Hippo/Warts signaling functions intrinsically to regulate tissue growth and organ size [3, 4], whereas systemic growth is controlled via antagonistic interactions of the steroid hormone ecdysone and nutrient-dependent insulin/insulin-like growth factor (IGF) (insulin) signaling [2, 5].

Developmental Biology: When Less Damage Causes More Harm.

Circadian clocks are important timekeepers of physiological processes. A new report shows that silencing the circadian clock specifically in steroid-producing cells of Drosophila disrupts development and causes lethality, and is more detrimental than having no clock at all.

The Lantibiotic NAI-107 Efficiently Rescues Drosophila melanogaster from Infection with Methicillin-Resistant Staphylococcus aureus USA300.

We used the fruit fly Drosophila melanogaster as a cost-effective in vivo model to evaluate the efficacy of novel antibacterial peptides and peptoids for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. A panel of peptides with known antibacterial activity in vitro and/or in vivo was tested in Drosophila Although most peptides and peptoids that were effective in vitro failed to rescue lethal effects of S. aureus infections in vivo, we found that two lantibiotics, nisin and NAI-107, rescued adult flies from fatal infections.

A Drosophila Genome-Wide Screen Identifies Regulators of Steroid Hormone Production and Developmental Timing.

Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis.

CCHamide-2 Is an Orexigenic Brain-Gut Peptide in Drosophila.

The neuroendocrine peptides CCHamide-1 and -2, encoded by the genes ccha1 and -2, are produced by endocrine cells in the midgut and by neurons in the brain of Drosophila melanogaster. Here, we used the CRISPR/Cas9 technique to disrupt the ccha1 and -2 genes and identify mutant phenotypes with a focus on ccha-2 mutants. We found that both larval and adult ccha2 mutants showed a significantly reduced food intake as measured in adult flies by the Capillary Feeding (CAFE) assay (up to 72% reduced food intake compared to wild-type).

The Neuropeptide Allatostatin A Regulates Metabolism and Feeding Decisions in Drosophila.

Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and energy mobilization are regulated by the glucagon-related adipokinetic hormone (AKH) and the Drosophila insulin-like peptides (DILPs). Here, we provide evidence that the Drosophila neuropeptide Allatostatin A (AstA) regulates AKH and DILP signaling.

Transcriptional control of steroid biosynthesis genes in the Drosophila prothoracic gland by ventral veins lacking and knirps.

Specialized endocrine cells produce and release steroid hormones that govern development, metabolism and reproduction. In order to synthesize steroids, all the genes in the biosynthetic pathway must be coordinately turned on in steroidogenic cells. In Drosophila, the steroid producing endocrine cells are located in the prothoracic gland (PG) that releases the steroid hormone ecdysone.

Dynamic feedback circuits function as a switch for shaping a maturation-inducing steroid pulse in Drosophila.

Steroid hormones trigger the onset of sexual maturation in animals by initiating genetic response programs that are determined by steroid pulse frequency, amplitude and duration. Although steroid pulses coordinate growth and timing of maturation during development, the mechanisms generating these pulses are not known. Here we show that the ecdysone steroid pulse that drives the juvenile-adult transition in Drosophila is determined by feedback circuits in the prothoracic gland (PG), the major steroid-producing tissue of insect larvae.