In Drosophila, glycogen is the main storage form of carbohydrates and is found in the body wall muscles and in the FB in late larval stages (Baker and Thummel, 2007; Garrido et al., 2015). In addition to glycogen, trehalose is synthesized in the FB and released into the hemolymph. Upon starvation, glycogen is mobilized to maintain the circulating sugar levels (Mattila et al., 2015; Yamada et al., 2018). In mammals, the sensing of sugar at intracellular levels is mediated by the heterodimer formed by the conserved bHLH-Zip transcription factors ChREBP (Carbohydrate Response Element Binding Protein) and MondoA, together with their common partner Mlx (Max-like protein X), which are activated by sugars and promote the conversion of sugars to lipids. They control most of the sugar-responsive genes as well as carbohydrate, amino acid and lipid metabolism (Havula and Hietakangas, 2012; Mattila et al., 2015). In Drosophila, the single orthologs of ChREBP/Mondo and Mlx are Mondo and Bigmax, respectively, and this transcriptional network is essential for sugar tolerance also in this organism. Accordingly, the Mondo-Bigmax deficient Drosophila larvae presents lethality on any diet containing high levels of sucrose, glucose or fructose (Havula et al., 2013). In addition to the regulation of metabolic genes, Mondo-Bigmax regulate the expression of the TGFβ/Activin ligand Dawdle (Daw), the Gli-similar transcription factor Sugarbabe and the orthologue of mammalian Kruppel-like factors 10 and 11, Cabut (Bartok et al., 2015; Mattila et al., 2015). As detailed in next sections, the intracellular glucose sensing by Mondo-Bigmax is coupled to systemic growth through Daw. Other nutrient sensors involved in sugar tolerance are the nuclear receptor Hnf4 (Hepatocyte nuclear factor 4) and the NAD⁺-dependent deacetylase Sirtuin 1 and 2 (Sirt1, Sirt2). Hnf4 plays a critical role in carbohydrate metabolism as shown by the Hnf4 mutant larvae, which display highly elevated circulating glucose and trehalose levels and defects in lipid homeostasis (Palanker et al., 2009; Palu and Thummel, 2016). Sirt2, is required in the FB to maintain glucose homeostasis and peripheral insulin sensitivity by deacetylating and stabilizing Hnf4 through protein interactions (Palu and Thummel, 2016). Moreover, Sirt1 negatively regulates TAG accumulation in the larval FB (Reis et al., 2010).

TAG is the main lipid form in the FB, which is synthesized from dietary carbohydrates, fatty acids or proteins and is stored in intracellular LDs. Similarly to mammals, LDs of different sizes belong to distinct functional classes, which differ in their properties owing to differential association with particular sets of LD-associated proteins (Wilfling et al., 2013). Characterization of the LD proteome at different stages uncovered that LD-associated proteins are different according to the functional complexity among LDs (Cermelli et al., 2006; Beller et al., 2010; Walther and Farese, 2012; Krahmer et al., 2013). The best characterized LD proteins in the FB during the larval life are Lsd-1 and Lsd-2 (Lipid storage droplet-1 and -2), homologous to the mammalian PAT domain protein family (Perilipin, ADRP, and TIP47) (Grönke et al., 2003; Teixeira et al., 2003). Lsd-2 is required for storage of TAG, whereas Lsd-1 stimulates TAG hydrolysis (Bi et al., 2012). The subproteome analysis of LDs of Drosophila FB identified 248 proteins (Beller et al., 2006). Most of them were involved in cellular metabolism but proteins have been identified with diverse biological functions, including intracellular transport, cell organization and cell biogenesis. For instance, the droplet-associated protein Sturkopf has a role in endocrine physiology regulation (Werthebach et al., 2019). The sturkopf mutant adults show a mild decrease in TAG storage levels. However, they fail to adjust their developmental rate to dietary yeast-to-sugar ratio changes, suggesting a function in insulin and juvenile hormone signalling activities. Moreover, distinct spatially LD populations have been described in Drosophila FB: the peripheral LDs, in contact with the plasma membrane, and the larger cytoplasmic medial LDs. The peripheral LD homeostasis is regulated by Snazarus (Snz), which binds to LDs and promotes TAG storage (Ugrankar et al., 2019).

Interestingly, the regulation of lipid homeostasis is coupled to FB development and growth. For example, Lipin, which converts phosphatidate to diacylglycerol, is required for normal FB development and TAG storage (Ugrankar et al., 2011). Loss of Lipin in Drosophila leads to severe defects in the development of the FB with changes in cell nucleus, mitochondria, autophagosome formation and size of LDs. Similarly, the Drosophila BMP-5,7 orthologue, glass bottom boat (gbb), is also required for the development of the larval FB and for maintaining proper metabolism. gbb mutants exhibit developmental delay and altered FB morphology with reduced total lipid, glucose and trehalose levels (Ballard et al., 2010). A recent study shows that the FB expression of the atypical MAP kinase, Erk7 (Extracellularly regulated kinase 7), inhibits cell autonomous and systemic growth and lipid storage. Erk7 expression is upregulated by fasting and, therefore, contributes to the adaptation to nutrient shortage. Erk7 regulates the subcellular localization of the chromatin binding protein No child left behind (Nclb), a growth-promoting downstream effector of mTOR, and inhibits the expression of the lipogenic transcription factor gene sugarbabe (Hasygar et al., 2021).

The energy storage in the FB during the larval development is required during low nutrient conditions and for the survival during the non-feeding periods, such as before and during metamorphosis and during the early stages of adulthood. The maintenance of the metabolic homeostasis requires the communication between the nutrient-storing FB and the consuming tissues.

In mammals, the main hormones that regulate the mobilization of fat and glucose are insulin and glucagon (Freychet P. 1990). Insulin is secreted by pancreatic β cells in response to high blood sugar levels, which triggers glycogen synthesis. Under low sugar levels pancreatic α cells release glucagon and triggers the breakdown of glycogen. Glucagon is also a lipolytic hormone that regulates fatty acids, ketone bodies and TAG.

In Drosophila, the insulin/glucagon axis is well conserved and involves the insulin-like peptides (Ilps) and the glucagon-like peptide Akh (Schaffer et al., 1990; Semaniuk et al., 2021). The mobilization of carbohydrate and lipid energy reserves from the FB in response to starvation is regulated by Akh/AkhR, which is produced by the neurosecretory cells of the corpora cardiaca (Kim and Rulifson, 2004; Lee and Park, 2004; Isabel et al., 2005). For carbohydrate mobilization, Akh/AkhR stimulates, through glycogen phosphorylase, the conversion of stored glycogen to hemolymph trehalose, which is important during the nonfeeding periods and during adult flight. The lipid mobilization through the action of Akh/AkhR, led to the phosphorylation of Lsd-1, which activates the Triglyceride Lipase (TGL) (Arrese et al., 2006; Arrese and Soulages, 2010). However, the role of Akh/AkhR is not completely elucidated as some reports suggest that Akh/AkhR is dispensable for lipid homeostasis in third instar larvae (Lee and Park, 2004; Gáliková et al., 2015). A recent report shows that, although in nutrient abundant conditions Akh/AkhR is dispensable during larval development, in low nutrient stress conditions Akh/AkhR signalling alters larval development and the adult metabolism and behaviour (Hughson et al., 2021).

In mammals, the mobilization of fatty acids from TAG storage is coordinated by the hormone-sensitive lipase (HSL) and the Patatin Like phospholipase Domain Containing 2 (PNPLA2, also known as ATGL) (Zimmermann et al., 2004; Young and Zechner, 2013). Interestingly, ATGL-dependent lipolysis of WAT triggers a systemic insulin release, which is essential for the replenishment of BAT energy storage in mice (Heine et al., 2018). In Drosophila, independently of Akh/AkhR signalling, the Brummer (Bmm) lipase, homolog of mammalian ATGL, converts the accumulated TAG to fatty acids (Grönke et al., 2005).

In Drosophila FB, the IIS and the TOR pathways regulate nutrient uptake, storage and metabolism. In addition, there is a crosstalk between the steroid hormone 20-hydroxyecdysone (ecdysone) and those pathways. Furthermore, the FB is the main sensor of internal oxygen levels that control organismal growth.

The Drosophila genome encodes eight Ilps (Grönke et al., 2010): Ilp, 2, 3 and 5 are produced by IPCs in the brain and are functionally comparable to insulin; Ilp6, produced by the FB, is related to mammalian Insulin Growth Factors, IGFs (Okamoto et al., 2009; Slaidina et al., 2009); Ilp7 and Ilp8 are relaxin-like peptides (Grönke et al., 2010). Similar to mammalian insulin, Ilps are able to regulate circulating levels of carbohydrates in the hemolymph. Insulin is a positive regulator of fat cell mass, acting through changes in both cell number and lipid storage (DiAngelo and Birnbaum, 2009). Ilp2 and Ilp5 regulate glycogen deposition, Ilp3 is responsible for the synthesis and release of trehalose into hemolymph and Ilp5 and Ilp7 regulate the synthesis of TAG (Kim and Rulifson, 2004; Post et al., 2018; Semaniuk et al., 2021). In addition, IIS/PI3K (Phosphatidylinositol 3-kinase) signalling coordinates nutritional status with endoreplicating tissues metabolism and growth (Britton et al., 2002). Thus, insulin regulates the critical weight, a checkpoint that occurs early in third instar larvae that determines the final body size (Mirth and Riddiford, 2007).

Mammals and Drosophila use the TOR pathway for cellular nutrient sensing, playing an important role in the balance of energy storage. The TOR kinase activity depends on amino acid availability and mediates protein synthesis, amino acid import, ribosome biogenesis and autophagy (Saxton and Sabatini, 2017). Consequently, Tor mutant larvae show reduced size and glucose and lipid storage levels, larvae showing a transparent phenotype (Colombani et al., 2003; Luong et al., 2006).

In addition, there is crosstalk between IIS and ecdysone. Ecdysone signalling in the FB antagonizes IIS and promotes autophagy (Rusten et al., 2004; Colombani et al., 2005). Furthermore, ecdysone modulates organismal growth through a FB relay that attenuates systemic insulin signalling (Colombani et al., 2005; Arquier et al., 2008; Honegger et al., 2008; Jin et al., 2012; Lee et al., 2018).

In Drosophila and other animals, the organisms require sensing the levels of oxygen to adapt their systemic growth to the environmental conditions. A central regulator for the maintenance of oxygen homeostasis is the hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor composed of the oxygen regulated HIF-1α and the constitutively expressed HIF-1β. In presence of oxygen, HIF-1α is hydroxylated by HIF prolyl hydroxylase (Hph), targeting it for ubiquitin-dependent proteasomal degradation. In hypoxia, HIF-1α is stabilized and induces the expression of target genes that regulate growth and metabolism (Semenza, 2014).

To link the organismal growth to the nutrient availability, the FB produces signalling molecules that promote or inhibit the insulin secretion from IPCs ( Figure 3 and Table 3 ). Some of these factors and neuropeptides are secreted in response to dietary fats and/or sugars such as Unpaired 2 (Upd2), Daw and CCHamide-2 (CCHa2).

Upd2, a JAK/STAT cytokine (Rajan and Perrimon, 2012), binds to its receptor Dome (Domeless) on GABAergic neurons, releases the inhibition of IPCs and promotes Ilp secretion. Recently, an essential role for adipose p53 in sensing nutrient stress and maintaining metabolic homeostasis has been reported (Ingaramo et al., 2020). Under nutrient deprivation and high-sugar diet, p53 is activated in the FB and represses the expression of Upd2. This AMP-activated protein kinase (AMPK)-dependent p53 activation leads to modulation of Ilp2 levels, systemic insulin/TOR signalling and autophagy induction (Ingaramo et al., 2020). Another response to the consumption of sugar is the release by the FB of the activin-like factor Daw, which promotes the secretion of Ilps through the TGF-β/activin receptor Baboon (Babo) (Ghosh and O’Connor, 2014). In addition, Daw released from the FB signals to the intestine where inhibits the expression of carbohydrases and lipases by enhancing Smad on X (Smox) levels (Chng et al., 2014). The sugar induced gene expression of Daw is mediated by Mondo-Bigmax, whereas Foxo (forkhead box, sub-group O) negatively regulates its expression (Bai et al., 2013; Mattila et al., 2015). A third mechanism by which carbohydrates promote Ilp expression and secretion is through CCHa2, a neuropeptide induced in the FB by proteins and sugars. When released, the CCHa2 peptide promotes the secretion of Ilp2 and Ilp5 via its receptor, CCHa2R, expressed in the IPCs (Ren et al., 2015; Sano et al., 2015).

TOR-dependent FB humoral signals couple Ilp2 and Ilp5 secretion from the IPCs with amino acid intake and some humoral factors are secreted in response to dietary amino acids such as Stunted (Sun), Eiger (Egr) and the Growth blocking peptides GBP1 and GBP2 (Colombani et al., 2003; Honegger et al., 2008; Géminard et al., 2009; Rajan and Perrimon, 2012; Ghosh and O’Connor, 2014; Sano et al., 2015; Agrawal et al., 2016; Delanoue et al., 2016; Koyama and Mirth, 2016). Interestingly, amino acid-dependent TOR signalling derived from the FB controls neural stem cell proliferation independent from IPCs-derived Ilps. In the developing central nervous system, embryonic and larval neuroblasts undergo proliferative phases, intercalated with periods of a quiescent state, that is reversible by dietary amino acids (Britton and Edgar, 1998). The TOR-mediated amino acid sensing induces a secreted FB signal that activates the expression of Ilps in glial cells. The local glial Ilps signal on adjacent neuroblasts via the IIS/PI3K/TOR pathway and control their reactivation (Chell and Brand, 2010; Sousa-Nunes et al., 2011).

Furthermore, ecdysone signalling in the FB modulates insulin dependent systemic growth through the regulation of Myc, microRNA miR-8 and ImpL2 (Ecdysone-inducible gene L2), a member of the immunoglobulin superfamily homolog to the Insulin-Like Growth Factor Binding Protein 7, IGFBP7 (Arquier et al., 2008; Honegger et al., 2008; Hyun et al., 2009; Delanoue et al., 2010; Jin et al., 2012; Lee et al., 2018).

The FB is a sensor tissue for amino acid levels and coordinates growth of peripheral tissues through a humoral mechanism (Colombani et al., 2003). Hence, the downregulation of the Slimfast (Slif) amino acid transporter within the FB is sufficient to induce a general reduction in the rate of larval growth (Colombani et al., 2003). In response to dietary amino acids, the peptide Sun is released from the FB (Delanoue et al., 2016). Sun binds to Methuselah (Mth), a secretin-incretin receptor on IPCs, and stimulates the secretion of Ilps. On the other hand, under conditions of low amino-acid concentrations, Egr, a Drosophila tumor necrosis factor alpha (TNF-alpha) orthologue is released from the larval FB (Agrawal et al., 2016). This cytokine signals through its receptor Grindelwald (Grnd) on the larval IPCs to activate the JNK-dependent inhibition of Ilps production. The expression of the endoplasmic reticulum (ER) degradation enhancing α-mannosidase-like protein 1 (Edem1) in the FB is also crucial for maintaining systemic insulin signalling, since its down-regulation results in the accumulation of Ilp2 in the IPCs and reduced systemic insulin signalling. The reduction in Edem1 levels is crucial for survival during starvation as lowering edem1 expression levels facilitates the activation Eiger on IPCs and the reduction in ISS. In addition, Edem1 regulates Upd2 to manage the metabolic status (Pathak and Varghese, 2021). Moreover, Growth-blocking peptides 1 and 2 (GBP1 and GBP2) are epidermal growth factors-like cytokines secreted by the FB upon availability of dietary amino acids (Koyama and Mirth, 2016). Recently, it was shown that these adipose tissue factors regulate Ilps secretion by silencing a pair of inhibitory neurons that synapse with IPCs (Meschi et al., 2019).

During late larval life, increased levels of ecdysone affect also systemic growth. Myc expression in the Drosophila FB triggers a cell autonomous mechanism that controls glucose and lipid metabolism to favour the storage of nutrients (Parisi et al., 2013). During the late third instar, ecdysone signalling represses Myc function inhibiting systemic growth. This suggests a humoral factor released downstream of Myc that relays information to control IIS (Delanoue et al., 2010). The ability of FB Myc activity to affect IPC Ilp2 secretion depends on stearoyl-CoA desaturase (Desat1) activity, an enzyme necessary for production of fatty acids and lipid biosynthesis (Parisi et al., 2013). The increased levels of ecdysone suppress the body growth also through the regulation of FB microRNA miR-8 (Hyun et al., 2009; Jin et al., 2012). Multiple peptide hormones regulated by miR-8 may contribute to Drosophila growth (Lee et al., 2015). Among them, the IGF-like factor Ilp6 and the Imaginal morphogenesis protein Late 2 (ImpL2) are upregulated in the FB of miR-8 null mutant larvae. Ilp6 expression from larval FB represses secretion of Ilp2 from IPCs and extends lifespan (Bai et al., 2012). Before and during pupariation or in response to starvation, Ilp6 communicates the FB with other organs. For example, it promotes the growth of imaginal discs, which gives rise to adult organs, and the lipid uptake in oenocytes, cell clusters of ectodermal origin that regulate lipid metabolism (Chatterjee et al., 2014). Nutritional restriction also increases the levels of ecdysone, which triggers the production of ImpL2 in the FB (Lee et al., 2018). In response to nutrient limitation, the FB nutrient sensor function, which restricts the growth of peripheral tissues, is complemented by the release of nutrients through autophagic degradation of the FB cytoplasm. This provides other tissues with a source of nutrients necessary for survival. Thus, under conditions of low TOR signalling, autophagy promotes normal cell function and survival (Scott et al., 2004).

To adapt the systemic growth to the environmental conditions, the FB integrates the oxygen and amino acids levels through the Hph/HIF-1α and Hph/TOR pathways. In hypoxia, the FB release HIF-1α-dependent humoral factors that inhibit Ilps expression and secretion from the IPCs, thereby restricting the systemic growth. Moreover, independently of HIF-1α, Hph is required for nutrient-dependent TOR activation (Texada et al., 2019). To allow adults viability in hypoxia, the larval FB inhibits TORC1 signalling and reorganizes the lipid storage (Lee et al., 2019). A recent study showed that FOXO is a hypoxia inducible factor that mediates tolerance to low oxygen by inducing immune-like responses in the FB (Barretto et al., 2020).

Similarly to the larval one, the adult FB is the central metabolic organ involved in the accumulation of fat and glycogen from caloric overload and in the mobilization of the stored fat during starvation or egg production (Lee and Park, 2004; Parra-Peralbo and Culi, 2011; Musselman et al., 2013; Mattila and Hietakangas, 2017; Zhao and Karpac, 2017; Weaver and Drummond-Barbosa, 2019). Not surprisingly, in females the FB has higher proportion of lipids than that in males (Johnson and Butterworth, 1985). In contrast to larval FB there are evidences suggesting the ability of adult FB to grow in order to accumulate lipids, in obese flies (DiAngelo and Birnbaum, 2009).

In the adult FB, Akh/AkhR signalling activates cAMP-responsive element binding (CREB) transcription factor (Song et al., 2017). CREB downregulation was shown to promote overeating and obesity in adult flies (Iijima et al., 2009). In addition, Akh/AkhR signalling modulates TAG content in adult FB through the store-operated calcium entry (SOCE) (Baumbach et al., 2014). Under short-term fasting conditions, Akh/AkhR signalling promotes lipase bmm gene expression by reducing Lkb1-Sik3 (Salt-inducible kinase 3)-HDAC4 (Histone deacetylase 4) signalling axis, probably through Foxo (Wang et al., 2011; Choi et al., 2015). Under long-term fasting conditions, however, the reduction of the Lkb1-Sik3 pathway to induce the lipolytic response is independent of Akh/AkhR. Conversely, insulin pathway induces Sik3 activity under feeding conditions, independently of Lkb1 (Choi et al., 2015) (Figure 4).

Recently, Relish known to be part of Imd pathway, as mentioned above, has been identified as a repressor of bmm gene expression through FOXO, by fasting-dependent histone deacetylation, during metabolic adaptation to fasting (Molaei et al., 2019).

Recently, an intestinal/neuronal/FB inter-organ communication has been described in adults to preserve energy homeostasis. In response to nutrients, enteroendocrine cells secrete systemically the hormone Bursicon α (Bursα), which binds to its neural receptor DLgr2. Bursα/DLgr2 signalling regulates energy metabolism through a neuronal relay that repress AKH production and, therefore, the subsequent modulation of AKHR signalling within the FB. The reduction of systemic Bursα/DLgr2 signalling leads to exacerbated glucose oxidation, strong lipodystrophy and depletion of energy stores with the consequent reduced organismal resistance to nutrient deprivation conditions (Scopelliti et al., 2019). Therefore, Bursicon inhibits the mobilization of glycogen storage under nutrient availability (Figure 4).

The overexpression in the adult FB of the gene foxo, encoding for the key target of the IIS pathway, leads to increased life span (Giannakou et al., 2004). Similarly, overexpression of the gene Sirt2 in adult FB increases longevity in both sexes. It also modulates the composition of the LD proteome, a plausible mechanism underlying extended longevity by Sirt2, as LDs regulate aging processes (Goldberg et al., 2009; Hoffmann et al., 2013). All these evidences point to a role of the adult AT in controlling longevity.

Tumors and their microenvironment can produce different circulating factors that cause cachexia, the wasting syndrome observed in advance cancer patients which is characterized by a general metabolic dysfunction that includes systemic inflammation, increased catabolism and lipolysis or proteolysis in muscles and AT (Ebadi and Mazurak, 2014). In Drosophila, two main models of cachexia have been described which show similarities with human patients (Figueroa-Clarevega and Bilder, 2015; Kwon et al., 2015; Song et al., 2019). One of the models is induced by activation of Yorkie (Yki), the Yap1 oncogen ortholog, in intestine stem cells that secrete a PDGF-and VEGF-related factor 1 (PvF1) ligand. Pvf1 leads to the pathological activation of ERK/MAPK signalling in peripheral tissues and induce wasting of muscles and AT (Song et al., 2019). The other model consists of the transplantation, in adult flies, of clones of eye disc cells mutant for the polarity gene scribble and ectopically expressing an activated form of Ras ^(V12) (Ras ^V12 , scrib ^−/− ). Interestingly, both tumor models secrete high levels of ImpL2 (Figueroa-Clarevega and Bilder, 2015; Kwon et al., 2015). Increased levels of circulating ImpL2 reduce systemic insulin signalling, which leads to reduction of nutrients uptake by muscle and adipose tissue, driving organ wasting. The Ras ^V12 , scrib ^−/− tumors also induce a systemic autophagy stress response in muscles and AT that mediates organ wasting (Katheder et al., 2017; Khezri et al., 20215). Recently, another wasting model in Drosophila, relates the FB remodelling and muscle detachment to the tumor-secreted matrix metalloproteinase 1 (Mmp1). Mmp1 can modulate TGFβ signalling in the FB and disrupts the basement membrane/extracellular matrix in FB and muscle (Lodge et al., 2021). All theses studies show that the conservation of the signalling pathways and the existing genetic tools, make of Drosophila an important model to study the process of organ wasting and to identify new molecular mechanisms involved in this process.