11 research outputs found
Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes
Lipoic acid (LA) is an antioxidant with therapeutic potential on several diseases such as diabetes and obesity. Hyperleptinemia and oxidative stress play a major role in the development of obesity-linked diseases. The aim of this study was to examine in vivo and in vitro the effects of LA on leptin production, as well as to elucidate the mechanisms and signalling pathways involved in LA actions. Methods and results: Dietary supplementation with LA decreased both circulating leptin, and adipose tissue leptin mRNA in rats. Treatment of 3T3-L1 adipocytes with LA caused a concentration-dependent inhibition of leptin secretion and gene expression. Moreover, LA stimulated the anaerobic utilization of glucose to lactate, which negatively correlated with leptin secretion. Furthermore, LA enhanced phosphorylation of Sp1 and inhibited Sp1 transcriptional activity in 3T3-L1 adipocytes. Moreover, LA inhibited Akt phosphorylation, a downstream target of phosphatidylinositol 3-kinase (PI3K). Treatment with the PI3K inhibitor LY294002 mimicked LA actions, dramatically inhibiting both leptin secretion and gene expression and stimulating Sp1 phosphorylation. Conclusion: All of these data suggest that the phosphorylation of Sp1 and the accompanying reduced DNA-binding activity are likely to be involved in the inhibition of leptin induced by LA, which could be mediated in part by the abrogation of the PI3K/Akt pathway
Oxidative stress and non-alcoholic fatty liver disease: effects of omega-3 fatty acid supplementation
Aging is a complex phenomenon characterized by the progressive loss of tissue and organ function. The oxidative-stress theory of aging postulates that age-associated functional losses are due to the accumulation of ROS-induced damage. Liver function impairment and non-alcoholic fatty liver disease (NAFLD) are common among the elderly. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and evolve to hepatic cirrhosis or hepatic carcinoma. Oxidative stress, lipotoxicity, and inflammation play a key role in the progression of NAFLD. A growing body of evidence supports the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFA), mainly docosahaexenoic (DHA) and eicosapentaenoic acid (EPA), on metabolic diseases based on their antioxidant and anti-inflammatory properties. Here, we performed a systematic review of clinical trials analyzing the efficacy of n-3 PUFA on both systemic oxidative stress and on NAFLD/NASH features in adults. As a matter of fact, it remains controversial whether n-3 PUFA are effective to counteract oxidative stress. On the other hand, data suggest that n-3 PUFA supplementation may be effective in the early stages of NAFLD, but not in patients with more severe NAFLD or NASH. Future perspectives and relevant aspects that should be considered when planning new randomized controlled trials are also discussed
Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice
Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to
chronic unresolved inflammation, which could be mediated by an impaired production
of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs,
Resolvins-Rvs,
Protectins-PDs,
and Maresins-MaRs.
Our aim was to characterize the
changes in BAT SPMs signatures and their association with BAT dysfunction during
aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic
acid (DHA)-rich
diet. Lipidomic, functional, and molecular studies were performed
in BAT of 2-and
18-month-
old
lean (CT) female mice and in 18-month-
old
diet-induced
obese (DIO) mice fed with a high-fat
diet (HFD), or a DHA-enriched
HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice,
while DHA partially restored them. Arachidonic acid (AA)-derived
LXs and DHA-derived
MaRs and PDs were the most abundant SPMs in BAT of young CT mice.Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice
compared to young CT mice. Some of the SPMs most significantly reduced in obese-aged
mice included LXB4, MaR2, 4S,14S-diHDHA,
10S,17S-diHDHA
(a.k.a. PDX),
and RvD6. In contrast, DHA increased DHA-derived
SPMs, without modifying LXs.
However, MicroPET studies showed that DHA was not able to counteract the impaired
cold exposure response in BAT of obese-aged
mice. Our data suggest that a
defective SPMs production could underlie the decrease of BAT activity observed in
obese-aged
mice, and highlight the relevance to further characterize the physiological
role and therapeutic potential of specific SPMs on BAT development and function
Effects of α-lipoic acid on lipid metabolism and mitochondrial biogenesis in adipocytes: study of the molecular mechanisms involved
α-lipoic acid (5-(1,2-dithiolan-3-yl)-pentanoic acid) is a natural occurring compound which possesses antioxidant properties. Moreover, anti-obesity properties in both rodents and humans have been attributed to α-lipoic acid being adipose tissue a target for this compound. In this context, the present study has demonstrated the ability of α-LA to modulate lipid metabolism in both murine and human white adipocytes. Thus, α-LA: 1) Inhibits fatty acids uptake (through CD36 downregulation); 2) Reduces fatty acids esterification into triglycerides (through DGAT1 reduction); 3) Decreases de novo lipogenesis (induced by inhibition of FAS, SCD1 and ACC mediated by AMPK activation); 4) Stimulates lipolysis (mainly mediated by the phosphorylation of HSL through cAMP-mediated activation of PKA, probably through the inhibition of AdPLA and PGE2; 5) Increases fatty acid oxidation machinery (CPT1 and ACOX) in white adipocytes; 6) Promotes mitochondrial biogenesis by the activation of PGC-1α mediated by SIRT1 and AMPK activation; and 7) Induces a brown-like remodelling in white subcutaneous adipocytes from overweight/obese subjects.
Taking together all of these facts suggest that α-LA remodels adipocyte metabolism towards oxidation rather than storage, and this could contribute to the anti-obesity properties of α-LA
Effects of α-lipoic acid on lipid metabolism and mitochondrial biogenesis in adipocytes: study of the molecular mechanisms involved
α-lipoic acid (5-(1,2-dithiolan-3-yl)-pentanoic acid) is a natural occurring compound which possesses antioxidant properties. Moreover, anti-obesity properties in both rodents and humans have been attributed to α-lipoic acid being adipose tissue a target for this compound. In this context, the present study has demonstrated the ability of α-LA to modulate lipid metabolism in both murine and human white adipocytes. Thus, α-LA: 1) Inhibits fatty acids uptake (through CD36 downregulation); 2) Reduces fatty acids esterification into triglycerides (through DGAT1 reduction); 3) Decreases de novo lipogenesis (induced by inhibition of FAS, SCD1 and ACC mediated by AMPK activation); 4) Stimulates lipolysis (mainly mediated by the phosphorylation of HSL through cAMP-mediated activation of PKA, probably through the inhibition of AdPLA and PGE2; 5) Increases fatty acid oxidation machinery (CPT1 and ACOX) in white adipocytes; 6) Promotes mitochondrial biogenesis by the activation of PGC-1α mediated by SIRT1 and AMPK activation; and 7) Induces a brown-like remodelling in white subcutaneous adipocytes from overweight/obese subjects.
Taking together all of these facts suggest that α-LA remodels adipocyte metabolism towards oxidation rather than storage, and this could contribute to the anti-obesity properties of α-LA
Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes
Lipoic acid (LA) is an antioxidant with therapeutic potential on several diseases such as diabetes and obesity. Hyperleptinemia and oxidative stress play a major role in the development of obesity-linked diseases. The aim of this study was to examine in vivo and in vitro the effects of LA on leptin production, as well as to elucidate the mechanisms and signalling pathways involved in LA actions. Methods and results: Dietary supplementation with LA decreased both circulating leptin, and adipose tissue leptin mRNA in rats. Treatment of 3T3-L1 adipocytes with LA caused a concentration-dependent inhibition of leptin secretion and gene expression. Moreover, LA stimulated the anaerobic utilization of glucose to lactate, which negatively correlated with leptin secretion. Furthermore, LA enhanced phosphorylation of Sp1 and inhibited Sp1 transcriptional activity in 3T3-L1 adipocytes. Moreover, LA inhibited Akt phosphorylation, a downstream target of phosphatidylinositol 3-kinase (PI3K). Treatment with the PI3K inhibitor LY294002 mimicked LA actions, dramatically inhibiting both leptin secretion and gene expression and stimulating Sp1 phosphorylation. Conclusion: All of these data suggest that the phosphorylation of Sp1 and the accompanying reduced DNA-binding activity are likely to be involved in the inhibition of leptin induced by LA, which could be mediated in part by the abrogation of the PI3K/Akt pathway
Oxidative stress and non-alcoholic fatty liver disease: effects of omega-3 fatty acid supplementation
Aging is a complex phenomenon characterized by the progressive loss of tissue and organ function. The oxidative-stress theory of aging postulates that age-associated functional losses are due to the accumulation of ROS-induced damage. Liver function impairment and non-alcoholic fatty liver disease (NAFLD) are common among the elderly. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and evolve to hepatic cirrhosis or hepatic carcinoma. Oxidative stress, lipotoxicity, and inflammation play a key role in the progression of NAFLD. A growing body of evidence supports the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFA), mainly docosahaexenoic (DHA) and eicosapentaenoic acid (EPA), on metabolic diseases based on their antioxidant and anti-inflammatory properties. Here, we performed a systematic review of clinical trials analyzing the efficacy of n-3 PUFA on both systemic oxidative stress and on NAFLD/NASH features in adults. As a matter of fact, it remains controversial whether n-3 PUFA are effective to counteract oxidative stress. On the other hand, data suggest that n-3 PUFA supplementation may be effective in the early stages of NAFLD, but not in patients with more severe NAFLD or NASH. Future perspectives and relevant aspects that should be considered when planning new randomized controlled trials are also discussed
Chronic docosahexaenoic acid supplementation improves metabolic plasticity in subcutaneous adipose tissue of aged obese female mice
This study aimed to characterize the potential beneficial effects of chronic docosahexaenoic acid (DHA) supplementation on restoring subcutaneous
white adipose tissue (scWAT) plasticity in obese aged female mice. Two-month-old female C57BL/6J mice received a control (CT) or a high fat diet (HFD)
for 4 months. Then, 6-month-old diet-induced obese (DIO) mice were distributed into the DIO and the DIOMEG group (fed with a DHA-enriched HFD)
up to 18 months. In scWAT, the DHA-enriched diet reduced the mean adipocyte size and reversed the upregulation of lipogenic genes induced by the
HFD, reaching values even lower than those observed in CT animals. DIO mice exhibited an up-regulation of lipolytic and fatty oxidation gene expressions
that was reversed in DHA-supplemented mice except for Cpt1a mRNA levels, which were higher in DIOMEG as compared to CT mice. DHA restored the
increase of proinflammatory genes observed in scWAT of DIO mice. While no changes were observed in total macrophage F4/80+/CD11b+ content, the DHA
treatment switched scWAT macrophages profile by reducing the M1 marker Cd11c and increasing the M2 marker CD206. These events occurred alongside
with a stimulation of beige adipocyte specific genes, the restoration of UCP1 and pAKT/AKT ratio, and a recovery of the HFD-induced Fgf21 upregulation. In
summary, DHA supplementation induced a metabolic remodeling of scWAT to a healthier phenotype in aged obese mice by modulating genes controlling
lipid accumulation in adipocytes, reducing the inflammatory status, and inducing beige adipocyte markers in obese aged mice
Chronic docosahexaenoic acid supplementation improves metabolic plasticity in subcutaneous adipose tissue of aged obese female mice
This study aimed to characterize the potential beneficial effects of chronic docosahexaenoic acid (DHA) supplementation on restoring subcutaneous
white adipose tissue (scWAT) plasticity in obese aged female mice. Two-month-old female C57BL/6J mice received a control (CT) or a high fat diet (HFD)
for 4 months. Then, 6-month-old diet-induced obese (DIO) mice were distributed into the DIO and the DIOMEG group (fed with a DHA-enriched HFD)
up to 18 months. In scWAT, the DHA-enriched diet reduced the mean adipocyte size and reversed the upregulation of lipogenic genes induced by the
HFD, reaching values even lower than those observed in CT animals. DIO mice exhibited an up-regulation of lipolytic and fatty oxidation gene expressions
that was reversed in DHA-supplemented mice except for Cpt1a mRNA levels, which were higher in DIOMEG as compared to CT mice. DHA restored the
increase of proinflammatory genes observed in scWAT of DIO mice. While no changes were observed in total macrophage F4/80+/CD11b+ content, the DHA
treatment switched scWAT macrophages profile by reducing the M1 marker Cd11c and increasing the M2 marker CD206. These events occurred alongside
with a stimulation of beige adipocyte specific genes, the restoration of UCP1 and pAKT/AKT ratio, and a recovery of the HFD-induced Fgf21 upregulation. In
summary, DHA supplementation induced a metabolic remodeling of scWAT to a healthier phenotype in aged obese mice by modulating genes controlling
lipid accumulation in adipocytes, reducing the inflammatory status, and inducing beige adipocyte markers in obese aged mice
Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice
Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to
chronic unresolved inflammation, which could be mediated by an impaired production
of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs,
Resolvins-Rvs,
Protectins-PDs,
and Maresins-MaRs.
Our aim was to characterize the
changes in BAT SPMs signatures and their association with BAT dysfunction during
aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic
acid (DHA)-rich
diet. Lipidomic, functional, and molecular studies were performed
in BAT of 2-and
18-month-
old
lean (CT) female mice and in 18-month-
old
diet-induced
obese (DIO) mice fed with a high-fat
diet (HFD), or a DHA-enriched
HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice,
while DHA partially restored them. Arachidonic acid (AA)-derived
LXs and DHA-derived
MaRs and PDs were the most abundant SPMs in BAT of young CT mice.Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice
compared to young CT mice. Some of the SPMs most significantly reduced in obese-aged
mice included LXB4, MaR2, 4S,14S-diHDHA,
10S,17S-diHDHA
(a.k.a. PDX),
and RvD6. In contrast, DHA increased DHA-derived
SPMs, without modifying LXs.
However, MicroPET studies showed that DHA was not able to counteract the impaired
cold exposure response in BAT of obese-aged
mice. Our data suggest that a
defective SPMs production could underlie the decrease of BAT activity observed in
obese-aged
mice, and highlight the relevance to further characterize the physiological
role and therapeutic potential of specific SPMs on BAT development and function