Obesity and Aging in the Drosophila Model
Cite: Christoph Heier, Svitlana Klishch, Olha Stilbytska, Uliana Semaniuk, Oleh Lushchak, The Drosophila model to interrogate triacylglycerol biology, Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Volume 1866, Issue 6, 2021, 158924, ISSN 1388-1981, https://doi.org/10.1016/j.bbalip.2021.158924.
Abstract
Researches of the relation between obesity and aging.
Obesity types:
- high-fat diet
- high-sugar diet
Energy Homeostasis in Drosophila nad Humans
Circulating and Stored Sources of Energy
Trehalose is the predominant sugar in flies (like the glycemia in human).
Open circulation system:
- In human, hyperglycemia leades vascular related diseases.
- But drosophila has open circulation system, which means it’s vascular would not affected by hyperglycemia.
Glycogen and lipid:
- Like mammals, extral energy material was stored in this way.
- Fat body consist of:
- polyploid
- multinucleate cells
Regulation of the Energy Balance by the Insulin-Like and Glucagon-Like Pathways
- Eight insulin-like peptides (Ilp1–8)
- Insulin-like receptor, InR.
- glycemia control: Ilp2,3,5 which from median neurosecretory cells of the brain
Regulation Pathway in Different Age:
median neurosecretory cells:
In laver:
- unable to sense circulating sugars
- regulated indirectly via the glucagon-like adipokinetic hormone (AKH), and several other hormones
In adult:
- It sense circulating glucose directly, via a mechanism similar to mammalian pancreatic β cells
Fat body
Fat body-specific manipulations of the InR indicate that analogously to human insulin, the fly IIS is a positive regulator of fat storage.
$InR\uparrow \ \to fat\ content\uparrow$
$IIS\downarrow \ \to fat\ content\uparrow$
IIS is responsible to glycogen storage.
IIS positively regulates glycogen synthesis.
An additional IIS-independent factor that promotes glycogen synthesis: ablation of the insulin-producing cells in the brain [32] or Ilp2-3,5 deficiency [33] lead to increased glycogen storage
AKH $\to$ hyperglycemic functions
Corpora cardiaca is an endocrine organ which could produce AKH
Laval: it was in ring gland.
Adult: migrate towards the thorax, and attaches to the esophagus, and sends axon-like projections toward the brain and crop
AKH:
- Mutatans: obeses.
- Over expression: lean phenotype.
- AKH does not induce catabolism of glycogen
- Glycogen levels rise upon Akh overexpression
- AKH is a hyperglycemic hormone (above two)
Lifespan in Different Types of Fly Obesity
HIhg Sugar Diet (HSD)-Induced Obesity
HSD diet: 1. 30% sugar; 2. 50–150% increased fat.
HSD effects:
- delays larval development
- reduces fecundity
- increases the age-independent mortality
Galenza, et al.[1]:
- Increased early mortality of flies
- Lifespan extension by 31%
Tânia Reis[2]:
- Early mortality has a bimodal distribution
- Lifespan was mildly increased
HSD increased the expression of the Ilp2,3, and 5 but InR are not response to it due to the increased levels of te Ilp-binding protein, lipocalin neural Lazarillo.
HSD-fed laval even resistance recombinant insulin.
Adult:
- IIS independently of insulin resistance
- causing decreased expression of Ilp2, 3, and 5
- the periphery remains insulin sensitive
- HSD-fed damage is simmilar to the Ilp2-3,5 triple mutants.
- HSD leads to dysfunction of pericardial nephrocytes (cells that simmilar like human kideny) which responsible to a shorter lifespan consequence.
- pharmacological inhibition of the hexosamine pathway extends the lifespan on HSD
Reduction of fly fitness:
- short-term exposure to HSD: causes a long-lasting reprogramming of the signaling in the fat body
- Sugar overload: numerous fat body-unrelated processes
- Increases endoplasmic reticulum stereoisomerism
- Decreases immunity, disrupts gut homeostasis, and reduces commensal bacteria
- HSD: causes heart disorders such as fibrillations, asystolic periods, and arrhythmias, leading to progressive heart failure
- Heart: hexosamine flux nad the cardiac-specific reduction of this pathway fully protects the heart from the HSD-induced pathologies
- HSD without additional water access: hyperosmolarity or hypovolemia; reduced body water content;
Dietary Restriction (DR) and the Paradox of Carbohydrate-Rich Diet
DR:
- intermittent fasting
- leads to increased, compensatory feeding
- protein leverage hypothesis: reduction of proteins increases appetite.
- restriction of certain nutrients
- food dilution.
Results: - protein restriction
- increases both lifespan and fat reserves
- high carbohydrate/low protein diet extends lifespan, whereas the caloric restriction itself does not
- DR reduces IIS activity
- Lifespan extension in flies is mediated by the target of rapamycin (TOR) signaling
- pharmacological inhibition of the TOR pathway by rapamycin not only extends lifespan, but also increases fat reserves
The HFD-Induced Obesity
HFD:
- 20% to 30% coconut oil, or 15% lard.
Leads to: - obesity, hyperglycemia
- reduced cardiac contractility, ectopic accumulation of fat in the heart
- other pathologies reminiscent of the diabetic cardiomyopathy
- associated with lifespan reduction
- Increases TGF-β signaling: responsible for the development of insulin resistance
- genetically enhanced lipolysis targeted to the heart is sufficient to prevent the HFD-triggered cardiac dysfunctions
- overactivation of immune responses
Obesity and Longevity in the Flies with Abrogated Reproduction
Reduced reproduction is associated with increased fat accumulation and longevity… numerous treatments that result in longevity and
excessive fat storage decrease fertility.
- some case: reduced reproduction correlates with obesity, but not with lifespan extension
- lifespan-extension associated with inhibition of breeding sometimes correlates with reduced fat reserves
ecdysteroids
- the only steroid hormones in Drosophila, which could mediate the trade-offs between reproduction and lifespan
- reduced ecdysteroid levels or mild RNAi against the Ecdysone receptor (EcR) extends lifespan in males
- regulate maturation; reproduction; EcR acts as a negative regulator of fat accumulation in larvae.
Genetic Links between Fat Storage and Lifespan
attenuation of the IIS and TOR signaling—also result in obesity… long-lived Methuselah (Mth) mutants have increased starvation resistance
Drosophila lines selected for longevity have increased resistance to starvation, suggesting higher energy reserves… increased starvation resistance resulted in increased fat storage, suggesting that longevity and obesity are determined by the same genetic variants… Nevertheless, there are also longevity selection lines without increased resistance to starvation
Lifespan in Other Genetic Models of Obesity
- severe obesity can be triggered via inhibition of either lipolytic pathway:
- lipase Brummer: doubling of the fat, in a mild reduction of lifespan.
- AKH hormone signaling: fat is increased by around 75–100%; lifespan is reduced only moderately
- obesity associated with euglycemia can be triggered by manipulations of calcium signaling via Stim RNAi
Pathways and Tissues Linking Lipid Metabolism and Lifespan
The IIS and AKH Endocrine Systems
- HSD and HFD increase expression of the fly homolog of leptin, unpaired2 (upd2).
- typical models of fly obesity also have reduced
insulin-like signaling. - HSD in adult flies reduces expression of all three brain-produced Ilps, while the periphery remains insulin-sensitive.
- HFD leads to reduced peripheral IIS, and to insulin resistance
- HSD in flies leads to increased signaling via the analogous AKH hormone.
- HSD in adult flies reduces expression
of all three brain-produced Ilps, while the periphery remains insulin-sensitive.
The Fat Body
- The expression of hh(Hedgehog) increases upon starvation, when the Hh pathway promotes mobilization of lipid reserves in the fat body
The Heart
- Under HFD, the apolipoproteins derived from cardiomyocytes, and not those produced by the fat body, are the predominate regulators of lipid metabolism
The Immune Cells
- HFD: enhanced production of the macrophage-derived cytokine Upd3,
- HFD shortens lifespan solely via the Upd3-dependent inflammatory response, and not via the increase in fat storage.
The Pericardial Nephrocytes
- HSD in flies leads to damage of the pericardial nephrocytes, which is a condition reminiscent of the diabetic nephropathy
The Gut
- The JNK pathway promotes further overproliferation of intestinal stem cells, which is directly responsible for lifespan shortening.
- Experimental inhibition of the JNK pathway, or overexpression of Mag in the intestine increases fat reserves in old flies
- Moderate inhibition of the JNK pathway also extends lifespan
Galenza, A.; Hutchinson, J.; Campbell, S.D.; Hazes, B.; Foley, E. Glucose modulates Drosophila longevity and
immunity independent of the microbiota. Biol. Open 2016, 5, 165–173. [CrossRef] [PubMed] ↩︎Reis, T. Effects of Synthetic Diets Enriched in Specific Nutrients on Drosophila Development, Body Fat, and Lifespan. PLoS ONE 2016, 11, e0146758. [CrossRef] [PubMed] ↩︎
Obesity and Aging in the Drosophila Model
