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First published online September 19, 2008
Journal of Experimental Biology 211, 3103-3110 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.016451
A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis
1 Department of Pediatrics and Pharmacology, University of Texas Southwestern
Medical School, Dallas, Texas 75390, USA
2 Department of Biological Chemistry, David Geffen School of Medicine,
University of California and the Howard Hughes Medical Institute, Los Angeles,
CA 90095, USA
* Author for correspondence (e-mail: kamal.bharucha{at}utsouthwestern.edu)
Accepted 23 July 2008
 |
Summary |
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 TOP Summary INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Key words: AKHR, fat body, obesity
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INTRODUCTION |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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; Leopold and Perrimon,
2007). Furthermore, the powerful genetic tools available in
Drosophila research make the fly a particularly tractable model
organism in which to probe metabolic pathways regulating energy balance. For
example, the Drosophila fat body, the major depot for carbohydrate
and lipid stores, is amenable to genetic manipulation specifically in either
larval or adult stages (e.g. see Lazareva
et al., 2007). Thus, it is becoming increasingly apparent that the
powerful tools of Drosophila genetics can be a gateway for a better
understanding of human metabolic disorders.
The molecular mechanisms by which humans and flies regulate the storage and
release of fuel molecules display remarkable parallels. For example,
Drosophila insulin-like peptides (dILPs) have a profound effect on
growth and energy homeostasis, recapitulating the role of the mammalian
insulin pathway (Rulifson et al.,
2002). dILPs bind to a single receptor (InR) and signal through
downstream effectors that are homologous to mammalian counterparts
(Garofalo, 2002;
Geminard et al., 2006;
Goberdhan and Wilson, 2003;
Lasko, 2002;
Wu and Brown, 2006). The
adipokinetic hormone (AKH) family of peptides is thought to play a key role in
catabolism in a variety of insect species
(Van der Horst, 2003). In
Drosophila, AKH is secreted by a small group of specialized
neuroendocrine cells, ablation of which results in a profound decrease in
circulating carbohydrate levels (Isabel et
al., 2005; Kim and Rulifson,
2004; Lee and Park,
2004). The AKH pathway has been proposed to be the functional
analog of the mammalian glucagon receptor. Strikingly, the molecular
mechanisms by which AKH- and dILP-secreting cells regulate carbohydrate
homeostasis are similar to those employed by insulin- and glucagon-secreting
pancreatic islet cells.
The fat body is the primary energy storage tissue in Drosophila
(Canavoso et al., 2001).
Glycogen and triglyceride comprise the major forms of energy storage for
carbohydrate and lipids, respectively. In insects, enzymatic pathways that
mediate both the synthesis and breakdown of glycogen have clear homology to
those found in mammals (Orgad et al.,
1987). Thus, the study of fly mutants with alterations in lipid
accumulation in the fat body raises the intriguing possibility that they will
provide insight into genetic determinants of human obesity and energy
homeostasis (Kulkarni and Perrimon,
2005; Murphy and Bloom,
2006). In mammals, the energy storage function of the fat body is
performed in separate tissues (such as liver and adipose). Because the fat
body plays a major role in both carbohydrate and lipid storage, research in
Drosophila could also illuminate the interplay between these two
major arms of metabolism within a single tissue.
Although several mutants of the Drosophila insulin pathway have
been studied, no mutants in the AKH pathway existed upon initiation of the
current work. Genetic manipulation of the AKH pathway had been limited to cell
ablation studies of AKH-producing corpora cardiaca cells
(Isabel et al., 2005;
Kim and Rulifson, 2004;
Lee and Park, 2004) and
ectopic expression of AKH in the fat body
(Lee and Park, 2004).
Biochemical studies have shown that AKH binds with high affinity to its
G-protein-coupled receptor (AKHR) (Park et
al., 2002; Staubli et al.,
2002). Furthermore, activation of AKHR activates many of the same
second messenger pathways as the mammalian glucagon receptor (such as
production of cAMP) (Gade and Auerswald,
2003; Unson,
2002). We envisioned that further analysis of the glucagon-like
AKH pathway in Drosophila could yield general insights into the
regulation of energy homeostasis by endocrine systems. To this end, we
generated mutations in Akhr and assessed their effects on metabolism,
starvation resistance, locomotor activity and feeding behavior. While this
work was being prepared for publication, an independent study of Akhr
was published (Gronke et al.,
2007).
|
MATERIALS AND METHODS |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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). Akhr cDNA (isoform PA as annotated in
FlyBase) was obtained using EST GH19447 (Bloomington) as a PCR template
(forward primer: cttgtcccaaaaaatggc and reverse primer: ttacttctggcggatcgg).
The resulting Akhr cDNA fragment was cloned into pUAST to generate
the UAS-Akhr plasmid that was used to generate transgenic flies. A
P-element excision screen was performed starting from
Akhrp
(y1w67c23;P{EPgy2}GRHREY11371; Bloomington
stock no. 20304) and a transposase containing stock
(y1w*; CyO, H{w[+mC]=PDelta2-3}HoP2.1/Bc1;
Bloomington stock no. 2078). Akhrrev and
Akhrnull flies were isolated by initially screening for
white-eyed flies and then further characterized by PCR using primers flanking
the P-element insertion and ATG transcription start sites. The
Akhrrev flies contain only a 17 bp remnant
(catgttatttcatcatg) at the original P-element (EY11371) insertion site and an
otherwise wild-type gene scaffold. The Akhrnull flies
contain an 
450 bp remnant of the excised P element fused to genomic
sequence 144 bp downstream of the original Akhr gene locus, with
removal of all intervening coding Akhr sequence, including the
transcription start site. The P-element remnant in
Akhrnull flies is fused to the genomic region downstream
of Akhr commencing with the following sequence: tttgaattgatatgcg. The
coding sequences of the flanking genes (Tsp and CG1118) were intact.
The flies were raised on standard medium (yeast–agar–molasses)
with 12 h:12 h light:dark cycle at 25°C. The fat body r4-Gal4
line (Lee and Park, 2004) was
obtained from J. Park (University of Tennessee, Knoxville, TN, USA) and
gustatory neuron-Gal4 lines (Wang et al.,
2004) were obtained from K. Scott (University of California,
Berkeley, CA, USA).
Genetic rescue experiments
Flies containing a UAS-Akhr insert on the third chromosome were
made homozygous null for Akhr, which is on the second chromosome.
Similarly, third chromosome inserts of fat body-Gal4 or neuronal-Gal4 stocks
were established in an Akhrnull background. The Gal4
transgenic stocks used in these experiments are described in this paper (i.e.
Akhr-Gal4) and have been previously published (see references above);
we independently confirmed the expression pattern for all published stocks.
Rescue stocks were derived by crossing the just described UAS-Akhr
and tissue-specific Gal4 stocks, allowing selective re-introduction of
Akhr (in an otherwise null background).
RT-PCR
Total RNA of a given genotype was isolated from 50 frozen flies (1-week-old
males) according to a modified solid-phase Qiagen (Valencia, CA, USA) RNeasy
Mini Kit (cat. no. 74104) protocol (DGRC, CGB Technical Report 2006-10). Fat
body-derived RNA was isolated using the preceding reagents from tissue pooled
from approximately 20 wandering third instar larvae dissected in cold PBS. A 5
g aliquot of total RNA was subsequently treated with DNAse I and cDNA was
prepared using Superscript II Reverse Transcriptase (Invitrogen, Carlsbad, CA,
USA). PCR was performed with primers to exon 5 (forward: ggactctacaacattcgc)
and exon 6 (reverse: cctcttccattcagcagc) of the Akhr gene.
Immunostaining
Fly brains were dissected and stained using previously described procedures
(Nern et al., 2005); images
were captured using a Zeiss LSM 510 confocal microscope. Mouse polyclonal AKHR
antibodies were generated by the ASU CIM Antibody Core (Tempe, AZ, USA).
Nile Red staining
Fat body cells were visualized using Nile Red staining, according to a
published protocol (Gronke et al.,
2005).
Starvation and locomotor assay
Male flies were individually placed in Drosophila Activity
Monitoring System (DAMS; Trikinetics, Waltham, MA, USA) testing chambers
(previously capped with 2% agarose at one end). The flies were grown on a 12
h:12 h light:dark cycle at 25°C; locomotor data were collected in the
dark, also at 25°C. Data were exported into Excel and average total
locomotor activity (as measured by the total number of recorded midline
crossings) and starvation resistance were calculated for each line
(N=16 per genotype). Starvation resistance was defined as the time of
death after initiation of food deprivation, estimated as the time of last
recorded midline crossing for a given fly.
Body size measurements
Digital images of adult wings were obtained at constant magnification.
Using the `magic lasso' tool in PhotoShop, the area (pixel count) of each wing
that was bounded by L4, L5, the anterior cross vein and the lateral wing
border was measured. Higher magnification images were obtained for wing cell
size measurements. A constant square area of each wing was highlighted in
PhotoShop and the hairs were counted as a surrogate measure of the number of
cells in that area. Mesothorax (French et
al., 1998) and foreleg femur lengths were measured in arbitrary
units, but the relative lengths of these measurements were preserved in the
normalization.
Triglyceride and glycogen measurements
For triglyceride measurements, 1-week-old male flies (N=10 for
each genotype) were homogenized for lipid extraction in 3 ml 2:1
chloroform:methanol. Total triglyceride content was determined using the Waco
L-Type TG kit (Richmond, VA, USA). For glycogen measurements, 1-week-old male
flies (N=40 in fed state; N=100 in starved state) were
homogenized in 2 ml buffer (0.01 mol l–1
KH2PO4, 1 mmol l–1 EDTA, pH 7.4). The
homogenate was spun for 15 min at 13,000g to remove fly debris. The
supernatant was aliquoted and stored at –80°C. The Sigma Starch
Assay Kit (SA-20; St Louis, MO, USA) employs a two-step enzymatic approach for
glycogen determination. In this assay, glycogen is first hydrolyzed by
incubation with amyloglucosidase; the resulting glucose monomers are treated
with hexokinase and the resulting NADPH generated is quantified
spectrophotometrically against a glucose standard curve.
Food intake assay
Batches of 1-week-old male flies (40–60 per run) were placed in
Terizaki plates (ISC Bioexpress, Kaysville, UT, USA; Cat. No. T-3017-2) in
which wells were filled with 10 mmol l–1 sucrose in 1% agar,
containing 0.5% (w/v) dye (FD&C No. 1; Spectrum Chemicals, Gardena, CA,
USA). The food intake of Akhrnull and
Akhrrev flies was calculated by quantifying the absorbance
of ingested dye according to a published protocol
(Libert et al., 2007). Fed
flies were exposed to the dye for approximately 6 h and the previously starved
flies for approximately 30 min. The longer time for fed flies was needed to
obtain adequate signal; previously starved flies required only 30 min exposure
to ingest a measurable quantity of dye-containing food.
|
RESULTS |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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). Akhrnull removes the entire coding
sequence with minimal disruption of adjacent genes. Only 150 bp of
genomic sequence downstream of Akhr is removed in
Akhrnull mutants, allowing phenotypes to be ascribed to
the specific removal of the Akhr gene. The revertant retains a small
remnant (<20 bp) of the 10 kb P element, but otherwise restores
wild-type gene structure (see Materials and methods section for a full
description). RT-PCR analysis of whole body homogenates demonstrated
Akhr mRNA transcript production in Akhrrev flies
but not in Akhrnull flies (data not shown). The
Akhrnull mutant is homozygous viable, allowing detailed
phenotypic analysis in the adult.
|
AKHR is expressed in the Drosophila fat body
To probe the expression pattern of AKHR, we generated transgenic flies that
expressed the transcriptional activator Gal4 under the control of a region of
DNA upstream of the Akhr gene likely to contain all the
transcriptional elements needed to recapitulate the expression pattern of
AKHR. Three independent lines were generated and were crossed to flies
carrying a reporter gene with the Gal4 binding sites (i.e. UAS) fused to GFP.
Robust expression of GFP was observed in the adult Drosophila fat
body (Fig. 1C–E), the
primary tissue for the storage of fuel molecules. Strong expression is
observed in the body cavity as well as the pericerebral region in all three
transgenic lines. Expression in the larval fat body was also observed (data
not shown). RT-PCR using RNA isolated from dissected fat body tissue confirmed
fat body expression. In addition, detection of Akhr fat body
expression by in situ hybridization has been reported in independent
work (Gronke et al., 2007).
The expression of AKHR in the fat body (as reflected by GFP reporter
fluorescence) is consistent with its expected role in regulating energy
homeostasis.
Akhr mutants have larger lipid and carbohydrate stores
We found that 1-week-old male Akhrnull mutants had at
least a twofold increase in triglyceride content when compared with
Akhrrev flies (Fig.
2A); Akhrp flies had intermediate triglyceride
levels under normal feeding conditions (data not shown). Furthermore, Nile Red
staining of dissected fat body tissue
(Gronke et al., 2005)
demonstrated markedly larger cells in Akhrnull flies than
in control Akhrrev flies
(Fig. 2B), consistent with the
total body lipid measurements. Akhrnull mutants showed a
modest increase in glycogen content compared to Akhrrev
control flies, but the difference became more apparent after 24 h of
starvation (Fig. 2C). Genetic
rescue experiments provide further confirmation of the carbohydrate phenotype.
Akhrnull mutants containing either the akhr-Gal4
or UAS-Akhr transgene had higher glycogen content than rescue flies
with both transgenes (both in the fed and starved states;
Fig. 2D).
|
Akhr mutants do not display any growth phenotypes, in contrast to
mutants in the Drosophila insulin signaling cascade (which have
decreased body and cell size; Fig.
2E) (Wu and Brown,
2006). Quantification of food intake in the fed state did not
reveal any gross differences in ingestion between Akhrnull
and Akhrrev flies (Fig.
2F). In fact, Akhrnull flies consumed less of
a dye-containing sucrose meal after 18–24 h of starvation. Thus, the
higher total body triglyceride content of Akhrnull flies
indicates an `obese' phenotype rather than arising from an increase in overall
body size. In humans, the term obesity is used as a measurement of mass
corrected for size. Because Akhrnull flies do not have any
growth phenotypes, we describe their higher total triglyceride content as
reflecting an obese phenotype rather than merely arising from an increase in
total body size. Intriguingly, based on our feeding experiments, the etiology
of the obese phenotypes is unlikely to arise from hyperphagic behavior of fed
Akhrnull mutants.
Akhr mutants are starvation resistant
Previous work in Drosophila has shown that starvation resistance
correlates strongly with lipid content
(Djawdan et al., 1998). We
therefore asked whether the higher triglyceride content of
Akhrnull flies confers a survival benefit during
starvation. A priori, if the AKH axis were the only pathway mediating
lipolysis, one would expect that mutant flies would not be starvation
resistant. However, we found Akhrnull flies were markedly
starvation resistant when compared with control flies
(Fig. 3A,B).
Akhrnull flies survived for about 3–4 days under
starvation conditions, whereas control flies lived for 1–2 days. Young
Akhrrev flies were more starvation resistant than older
flies, but young Akhrnull flies were as starvation
resistant as their older counterparts (Fig.
3B). It has been shown that larval fat body cells can persist in
the newly emerged adult (Aguila et al.,
2007). We have observed that the older mutant and revertant flies
lack the characteristically dissociable residual larval fat body cells of
younger flies. Taken together, these results suggest that
Akhrnull flies have a higher triglyceride content (and are
thus more starvation resistant) than Akhrrev flies because
of continued accumulation of lipid stores during the initial days of
adulthood.
|
We observed that after 48 h of starvation, nearly all revertant flies do not survive, in contrast to null mutant flies (see Fig. 3A for a quantification of starvation resistance profiles). In addition, we found that Akhrnull flies were fertile even after 48 h of starvation (data not shown), a time point at which nearly all wild-type flies are dead. Thus, the starvation resistant Akhrnull mutant flies can be maintained and propagated, despite being subjected to a potentially lethal environmental stressor. Akhrnull flies retain the ability to mobilize triglyceride but have significant stores even after 72 h of starvation, around the average time of death (Fig. 3C).
Decreased locomotor activity does not contribute to the starvation resistance of Akhr mutants
AKH is thought to play a role in modulating locomotor activity, as ablation
of AKH cells decreased locomotor activity under starvation conditions
(Isabel et al., 2005;
Lee and Park, 2004). The
starvation resistance of Akhr mutant flies could thus also reflect a
decrease in energy expenditure resulting from reduced locomotion. To ascertain
whether the starvation resistance of Akhrnull flies was
affected by decreased energy expenditure in locomotion, we monitored the
activity of individual revertant and mutant flies. One-week-old male
Akhrnull mutants in the fed state had no obvious defects
in locomotor behavior or circadian rhythm
(Fig. 3D). Importantly, no
statistically significant differences were seen between
Akhrnull and Akhrrev flies during the
first 24 h of starvation (Fig.
3E), a time point at which the vast majority of
Akhrrev flies were still alive. As previous studies, in
which AKH-secreting cells were ablated, suggested a role for AKH in regulating
locomotion under starvation conditions, we were surprised that loss of AKHR
did not affect locomotion. Although the underlying reason for this discrepancy
is not known, locomotor activity may be regulated by other hormones released
from AKH-secreting endocrine cells or another AKH receptor. In summary, these
data indicate that there is no contribution of abnormal locomotor activity to
the starvation resistant phenotypes of AKHR mutant flies.
AKHR is expressed in attractive gustatory neurons
We asked whether AKHR is expressed in the nervous system, as many peptides
hormones (and their receptors) have been shown to be critical for regulating
energy homeostasis and food intake in both insects and mammals
(Schwartz and Porte, 2005;
Wu et al., 2005). We observed
an intriguing expression pattern of AKHR in a subset of neurons in the adult
subesophageal ganglion (Fig.
4A–F), a site of projection for the majority of peripheral
gustatory neurons in Drosophila
(Amrein and Thorne, 2005;
Scott, 2005). A similar
expression pattern was observed in three independent transgenic lines.
However, verification of gustatory neuronal expression by in situ
hybridization was unsuccessful, as is the case for the majority of published
gustatory neuron-Gal4 transgenic lines. Unfortunately, antibody staining also
failed to give independent evidence for gustatory neuron expression. As
additional evidence for Akhr expression in the gustatory system,
Akhr was independently identified in a genome-wide microarray screen
for genes specifically expressed in the Drosophila gustatory system;
the Akhr gene mRNA transcript was found to be significantly
downregulated (by 2.942-fold; Student's t-test, P value
<0.01) in poxn mutants (which lack gustatory neurons) when
compared to heterozygous controls (P. Cameron and K. Scott, personal
communication).
|
Recent work has demonstrated that Drosophila gustatory neurons are functionally segregated into neurons that mediate attractive taste and aversive taste modalities. Interestingly, immunohistochemical double labeling with markers for different subclasses of gustatory neurons indicated that AKHR is expressed in neurons associated with attractive taste (e.g. Gr5a-expressing neurons; Fig. 4A–C), but strictly excluded from neurons mediating aversive taste (e.g. Gr66a-expressing neurons; Fig. 4D–F). We postulate that additional AKHR-expressing neurons probably represent other gustatory neurons mediating attractive taste. Taken together, the labeling studies indicate that AKHR is expressed in a highly selective fashion in only a subset of gustatory neurons, strictly excluded from all neurons known to be associated with aversive taste. Given the co-expression in a major subset of attractive-gustatory neurons, an intriguing possibility is that AKHR may be expressed in all neurons mediating attractive taste.
Fat body AKHR expression mediates metabolic phenotypes
To determine whether AKHR expression is required in the fat body or the
nervous system to mediate starvation resistance, we performed genetic rescue
experiments. In these experiments, Akhr expression was induced in
either the fat body or Gr5a gustatory neurons, in an otherwise
Akhr homozygous null mutant background (see the Materials and methods
section for a more detailed description). A dramatic decrease in starvation
resistance in Akhrnull mutants was observed after
expressing AKHR under the control of a fat body-Gal4 driver
(r4-Gal4; Fig. 4G)
(Lee, 2004). Similar rescue
experiments using Gr5a-Gal4, which drives Gal4 expression in a
majority of attractive-gustatory neurons, did not revert starvation resistance
(Wang, 2004). Fat body AKHR
expression also greatly reduced triglyceride content
(Fig. 4H). Our data suggest
that the regulation of total body triglyceride content is probably independent
of gustatory AKHR expression. In summary, genetic rescue experiments
demonstrate that manipulation of expression of AKHR in the fat body is
sufficient to modulate triglyceride content and starvation resistance.
|
DISCUSSION |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Other lipolytic mechanisms (independent of the AKH pathway) must exist in
Drosophila that enable Akhr mutants to utilize their
triglyceride stores and affect their starvation resistance. Recently, the AKH
and brummer lipase pathways were shown to be two major pathways
regulating lipolysis in Drosophila
(Gronke et al., 2007), but
they concluded that AKHR does not affect carbohydrate homeostasis. Here, in
striking contrast, we demonstrate that AKHR affects both total body
carbohydrate and lipid content. In the fed state, the percentage differences
in glycogen content between Akhrnull and
Akhrrev flies were not as pronounced as the differences in
lipid content, perhaps accounting for this discrepancy. However, we show that
differences in glycogen content between Akhrnull and
Akhrrev flies are more readily apparent after 24 h of
starvation. Our genetic rescue experiments provide further support for the
effect of Akhr expression on carbohydrate homeostasis. Because
Akhr mutants (and brummer mutants) retain their ability to
access their glycogen stores, we predict that additional pathways exist that
regulate carbohydrate homeostasis.
The selective expression of Akhr in gustatory neurons that mediate
attractive taste raises the interesting possibility that the AKH pathway
coordinates a fly's response to hunger in two ways: (1) by mobilizing internal
energy stores by its action on the fat body, and (2) increasing food intake by
its action on attractive-gustatory neurons. Starved Akhr mutants
display decreased food intake when re-introduced to food. However, genetic
rescue experiments (using flies of the same genotype as those used for rescue
of metabolic phenotypes) did not allow us to definitively attribute this
altered behavior to loss of AKHR function. Therefore, we cannot rigorously
exclude the possibility that the observed feeding behavior results from a
background effect. Nonetheless, it is intriguing to speculate that activation
of AKHR in the gustatory system promotes food intake in the hungry fly.
Further work will be needed to delineate the role of gustatory Akhr
expression in the context of an emerging picture of the Drosophila
neuronal feeding circuit (Melcher and
Pankratz, 2005).
Modulation of energy homeostasis by the AKH pathway
Genes that modulate the retention of fuel molecules can provide an adaptive
survival benefit during periods of decreased food availability
(Neel, 1962;
Speakman, 2004). Our results
are consistent with the idea that specific genetic mutations in
Drosophila can serve to prolong long-term survival when flies are
challenged with food deprivation. There is evidence that selective pressures
can be used to increase the triglyceride content of flies both in nature and
in the laboratory. For example, naturally occurring mutants of the
adipose gene have higher triglyceride stores and are starvation
resistant (Hader et al.,
2003). In addition, flies with higher triglyceride stores can be
generated by selecting for starvation-resistant phenotypes over several
generations (Baldal et al.,
2006; Djawdan et al.,
1998; Hoffmann and Harshman,
1999). Overall, more work is needed to understand better how
specific genetic mechanisms contribute to the adaptation of
Drosophila to specific ecological niches differing in food
availability (Hoffmann and Weeks,
2007; Montooth et al.,
2003; Reaume and Sokolowski,
2006).
Over the approximately 600 million years of evolution that separate humans
from flies from common urbilaterial ancestors
(De Robertis and Sasai, 1996),
mammals have evolved discrete liver and adipose tissues that have energy
storage functions performed jointly by the Drosophila fat body. Thus,
AKHR expression in the fat body is uniquely poised to control mobilization of
both carbohydrates and lipids. Mammals may require a more elaborate array of
endocrine signals that coordinate carbohydrate and lipid homeostasis during
periods of food deprivation. For example, specific genetic manipulation of the
mammalian glucagon pathway is rendered difficult by the complex structure of
the preproglucagon gene (Drucker,
2001). Although murine glucagon receptor knockouts have abnormal
carbohydrate metabolism, no obese phenotypes have been observed
(Conarello et al., 2007;
Gelling et al., 2003;
Parker et al., 2002).
Significantly, these results are confounded by upregulation of other hormone
pathways. Thus, Drosophila offers a genetically tractable model
organism to dissect pathways involved with energy mobilization.
We anticipate that further study of the AKHR pathway will provide a better
understanding of the downstream signaling components regulating glycogenolysis
and lipolysis that are conserved between flies and mammals. In addition, the
power of forward genetic screens in the Drosophila may uncover other
determinants of energy homeostasis that have relevance to the study of human
disorders of lipid and carbohydrate metabolism, such as obesity and diabetes
(Gronke et al., 2005;
Ruden et al., 2005).
|
Acknowledgments |
|---|
|
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