Autophagy couteracts weight gain, lipotoxicity and pancreatic β-cell death upon hypercaloric pro-diabetic regimens

Fernández, Álvaro F.; Bárcena, Clea; Martínez-García, Gemma G.; Tamargo‐Gómez, Isaac; Suárez, María Fernanda; Pietrocola, Federico; Castoldi, Francesca; Esteban, Lorena; Sierra‐Filardi, Elena; Boya, Patricia; López-Otı́n, Carlos; Kroemer, Guido; Mariño, Guillermo

doi:10.1038/cddis.2017.373

Cited by 82 publications

(76 citation statements)

References 48 publications

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“…Of note, autophagy is required for full weight loss upon acute starvation and counteracts weight gain-and obesityrelated pathologies in mice fed hypercaloric diets. Spermidine attenuated weight gain and the comorbidities of obesity induced by hypercaloric regimens, correlating with autophagy induction in WAT (76).…”

Section: Polyamines In Metabolic Syndromesmentioning

confidence: 85%

Spermidine in health and disease

Madeo

Eisenberg

Pietrocola

et al. 2018

Science

Self Cite

705

633

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Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction mimetics, which are defined as agents that mimic the beneficial effects of dietary restriction while limiting its detrimental effects. One such agent, the natural polyamine spermidine, has prominent cardioprotective and neuroprotective effects and stimulates anticancer immunosurveillance in rodent models. Moreover, dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Spermidine preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence. Mechanistically, it shares the molecular pathways engaged by other caloric restriction mimetics: It induces protein deacetylation and depends on functional autophagy. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.

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Section: Polyamines In Metabolic Syndromesmentioning

confidence: 85%

Spermidine in health and disease

Madeo

Eisenberg

Pietrocola

et al. 2018

Science

Self Cite

705

633

View full text Add to dashboard Cite

show abstract

“…Although formal proof for this assertion is missing, it appears logical that obesity acts as a major accelerator of aging and age-related diseases (including cancer and cardiovascular diseases) due to the chronic inhibition of autophagy [95]. In mice, partial autophagy defects mediated by knockout of Atg4b (genotype: Atg4b -/-) or haploinsufficiency of Atg7 (genotype: Atg5b -/-) predispose to the induction of obesity by high sucrose or high-fat diets, respectively [96,97]. Logically, it may be attempted to increase autophagic flux to increase energy expenditure and to interrupt the obesity-associated positive feedback loops resulting in ever-more increased appetite and adipogenesis to avoid metabolic syndrome and to retard the manifestation of comorbidities such as diabetes and hepatosteatosis.…”

Section: Obesitymentioning

confidence: 99%

Therapeutic modulation of autophagy: which disease comes first?

Maiuri

Kroemer

2019

Cell Death Differ

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The relentless efforts of thousands of researchers have allowed deciphering the molecular machinery that regulates and executes autophagy, thus identifying multiple molecular targets to enhance or block the process, rendering autophagy "druggable". Autophagy inhibition may be useful for preserving the life of cells that otherwise would succumb to excessive self-digestion. Moreover, autophagy blockade may reduce the fitness of cancer cells or interrupt metabolic circuitries required for their growth. Autophagy stimulation is probably useful for the prevention or treatment of aging, cancer (when stimulation of immunosurveillance is the therapeutic goal), cardiovascular disease, cystic fibrosis, infection by intracellular pathogens, obesity, and intoxication by heavy metals, just to mention a few examples. Epidemiological evidence suggests broad health-improving effects for lifestyles, micronutrients, and drugs that favor autophagy. In this review, we discuss the role of autophagy in disease pathogenesis while focusing on the question, which disease will become the first clinically approved indication for therapeutic autophagy modulation. Facts • Autophagy is one of the best-studied phenomena in cell biology. Drugs for enhancing or inhibiting general or specific autophagy are being developed. • Acquired or genetically determined alterations in autophagic flux are involved in multiple pathologies across the entire spectrum of human diseases. • Autophagy inhibition might be useful for the avoidance of unwarranted autophagy-dependent cell death. • Chronic autophagy stimulation has a positive impact on preclinical models of aging and multiple distinct agedependent diseases, including arteriosclerosis, cancer, and neurodegeneration. Acute autophagy stimulation also has organ-protective effects in models of ischemia or intoxication.

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“…Adipocytes in visceral fat of Atg4b KO mice, which manifest limited autophagic activity, were recently found to undergo a larger increase in size in response to feeding with a high‐calorie diet compared with those in control mice. In addition, pharmacological stimulation of autophagy with spermidine resulted in an increase in the level of autophagy and a decrease in cell size in visceral fat of WT mice.…”

Section: Discussionmentioning

confidence: 99%

Fat‐specific protein 27α inhibits autophagy‐dependent lipid droplet breakdown in white adipocytes

Nakajima

Nishimoto

Tateya

et al. 2019

J of Diabetes Invest

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Aims/IntroductionFat‐specific protein 27 (FSP27) α is the major isoform of FSP27 in white adipose tissue (WAT), and is essential for large unilocular lipid droplet (LD) formation in white adipocytes. In contrast, FSP27β is abundantly expressed in brown adipose tissue (BAT), and plays an important role in small multilocular LD formation. In FSP27 KO mice in which FSP27α and β are both depleted, WAT is characterized by multilocular LD formation, and by increased mitochondrial abundance and energy expenditure, whereas BAT conversely manifests large oligolocular LDs and reduced energy expenditure.Materials and MethodsWe investigated the effects of autophagy in WAT and BAT of wild type (WT) and FSP27 knockout (KO) mice. In addition, we examined the effects of FSP27α and FSP27β to the induction of autophagy in COS cells.ResultsFood deprivation induced autophagy in BAT of WT mice, as well as in WAT of FSP27 KO mice, suggesting that enhanced autophagy is characteristic of adipocytes with small multilocular LDs. Pharmacological inhibition of autophagy attenuated the fasting‐induced loss of LD area in adipocytes with small multilocular LDs (BAT of WT mice and WAT of FSP27 KO mice), without affecting that in adipocytes with large unilocular or oligolocular LDs (WAT of WT mice or in BAT of FSP27 KO mice). Overexpression of FSP27α inhibited autophagy induction by serum deprivation in COS cells, whereas that of FSP27β had no such effect.ConclusionsThe present results thus showed that FSP27α inhibits autophagy and might thereby contribute to the energy‐storage function of WAT.

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Autophagy couteracts weight gain, lipotoxicity and pancreatic β-cell death upon hypercaloric pro-diabetic regimens

Cited by 82 publications

References 48 publications

Spermidine in health and disease

Spermidine in health and disease

Therapeutic modulation of autophagy: which disease comes first?

Fat‐specific protein 27α inhibits autophagy‐dependent lipid droplet breakdown in white adipocytes

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