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. 2017 Jan;58(1):72-80.
doi: 10.1194/jlr.M069385. Epub 2016 Nov 24.

Ectopic fat deposition contributes to age-associated pathology in Caenorhabditis elegans

Konstantinos Palikaras  1 , Meropi Mari  1 , Barbara Petanidou  2   3 , Angela Pasparaki  1 , George Filippidis  4 , Nektarios Tavernarakis  5   6
Affiliations

Ectopic fat deposition contributes to age-associated pathology in Caenorhabditis elegans

Konstantinos Palikaras et al. J Lipid Res. 2017 Jan.

Abstract

Age-dependent collapse of lipid homeostasis results in spillover of lipids and excessive fat deposition in nonadipose tissues. Ectopic fat contributes to lipotoxicity and has been implicated in the development of a metabolic syndrome that increases risk of age-associated diseases. However, the molecular mechanisms coupling ectopic fat accumulation with aging remain obscure. Here, we use nonlinear imaging modalities to visualize and quantify age-dependent ectopic lipid accumulation in Caenorhabditis elegans We find that aging is accompanied by pronounced deposition of lipids in nonadipose tissues, including the nervous system. Importantly, interventions that promote longevity such as low insulin signaling, germ-line loss, and dietary restriction, which effectively delay aging in evolutionary divergent organisms, diminish the rate of ectopic fat accumulation and the size of lipid droplets. Suppression of lipotoxic accumulation of fat in heterologous tissues is dependent on helix-loop-helix (HLH)-30/transcription factor EB (TFEB) and autophagy. Our findings in their totality highlight the pivotal role of HLH-30/TFEB and autophagic processes in the maintenance of lipid homeostasis during aging, in addition to establishing nonlinear imaging as a powerful tool for monitoring ectopic lipid droplet deposition in vivo.

Keywords: aging; imaging; lipotoxicity; nonlinear phenomena; second harmonic generation; third harmonic generation.

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Figures

Fig. 1.
Fig. 1.
THG specifically visualizes ectopic fat deposition in C. elegans. THG signals (blue) colocalize with Nile Red (red) labeled lipids in C. elegans, visualized by TPEF. Images of pharyngeal area of 1-day-old wild-type animals are shown. Scale bar denotes 30 μm.
Fig. 2.
Fig. 2.
SHG and THG imaging reveal ectopic lipid droplet accumulation during aging. Simultaneous SHG (magenta) and THG (blue) signals visualize fat storage in body wall muscles (z-sequence of 2D slices divided by 2 μm) (A) and z-projections to maximum intensity of 15 slices divided by 2 μm of pharyngeal muscles (B) of wild-type nematodes during aging. C: Quantification of THG signals. n = 12 for each time point. *** P < 0.001, one-way ANOVA followed by Tukey HSD post hoc test; error bars denote standard error of the mean. Scale bars denote 30 μm.
Fig. 3.
Fig. 3.
Gradual lipid droplet accumulation in C. elegans nervous system with age. Coupling of TPEF (green) and THG (blue) imaging reveals lipid droplet accumulation in CEPsh (A, B) and around neuronal cell bodies and along neuronal processes of CEP dopaminergic neurons (C, D) during aging. The images are z-projections of 18 slices to maximum intensity divided by 2 μm. Scale bars denote 30 μm.
Fig. 4.
Fig. 4.
Longevity-promoting interventions prevent age-dependent ectopic fat deposition. A: The rate of ectopic lipid content in the pharynx of wild-type animals is significantly increased compared with eat-2(ad465), daf-2(e1370), and glp-1(e2141) mutants during aging. The division of THG signal values, at day 1 and day 9, by the day 1 THG signal values of each strain, respectively, depicts the rate of ectopic lipid content. B: Quantification of lipid droplet sizes in long-lived animals during aging. n = 12 for each genetic background and time point. NS, P > 0.05, *** P < 0.001, one-way ANOVA followed by Tukey HSD post hoc test; error bars denote standard error of the mean.
Fig. 5.
Fig. 5.
HLH-30 and autophagy preserve lipid homeostasis in eat-2(ad465) mutants. A, B: Quantification of THG signals in the pharyngeal muscle cells of wild-type and eat-2(ad465) animals upon knockdown of (A) hlh-30 or (B) lgg-1. n = 12 for each genetic background and time point. NS, P > 0.05, *** P < 0.001, one-way ANOVA followed by Tukey HSD post hoc test; error bars denote standard error of the mean.
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