The inhibition of fat cell proliferation by n-3 fatty acids in dietary obese mice

ABSTRACT: BACKGROUND: Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) of marine origin exert multiple beneficial effects on health. Our previous study in mice showed that reduction of adiposity by LC n-3 PUFA was associated with both, a shift in adipose tissue metabolism and a decrease in tissue cellularity. The aim of this study was to further characterize the effects of LC n-3 PUFA on fat cell proliferation and differentiation in obese mice. METHODS: A model of inducible and reversible lipoatrophy (aP2-Cre-ERT2 PPARgammaL2/L2 mice) was used, in which the death of mature adipocytes could be achieved by a selective ablation of peroxisome proliferator-activated receptor gamma in response to i.p. injection of tamoxifen. Before the injection, obesity was induced in male mice by 8-week-feeding a corn oil-based high-fat diet (cHF) and, subsequently, mice were randomly assigned (day 0) to one of the following groups: (i) mice injected by corn-oil-vehicle only, i.e."control" mice, and fed cHF; (ii) mice injected by tamoxifen in corn oil, i.e. "mutant" mice, fed cHF; (iii) control mice fed cHF diet with 15% of dietary lipids replaced by LC n-3 PUFA concentrate (cHF+F); and (iv) mutant mice fed cHF+F. Blood and tissue samples were collected at days 14 and 42. RESULTS: Mutant mice achieved a maximum weight loss within 10 days post-injection, followed by a compensatory body weight gain, which was significantly faster in the cHF as compared with the cHF+F mutant mice. Also in control mice, body weight gain was depressed in response to dietary LC n-3 PUFA. At day 42, body weights in all groups stabilized, with no significant differences in adipocyte size between the groups, although body weight and adiposity was lower in the cHF+F as compared with the cHF mice, with a stronger effect in the mutant than in control mice. Gene expression analysis documented depression of adipocyte maturation during the reconstitution of adipose tissue in the cHF+F mutant mice. CONCLUSION: Dietary LC n-3 PUFA could reduce both hypertrophy and hyperplasia of fat cells in vivo. Results are in agreement with the involvement of fat cell turnover in control of adiposity

Molekulární mechanismy n-3 polynenasycených mastných kyselin

Adipose tissue and its hormones have an irreplaceable role in the physiology of mammals. The imbalance between energy intake and energy expenditure leads to the expansion of adipose tissue and changes in its secretion profile. With obesity are associated diseases including cardiovascular diseases, dyslipidemia, hypertension and insulin resistance, one of the major public health issues. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) from marine origin, mainly eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids exert numerous beneficial effects, such as improvements of lipid metabolism and prevention of obesity and diabetes. Studies with obesity-prone model mice (C57BL/6) provide us important knowledge regarding their effect on mammalian tissues and to test potential therapeutic interventions. The thesis is based on five published studies (A-E). Three studies are focused on white adipose tissue. In these works we proved that adipose tissue is a flexible organ and LC n- 3 PUFAs are potent regulators of adipose tissue biology. Our results document that LC n- 3 PUFAs affect adipose tissue mass by a mechanism, which depends on counteraction of both, differentiation and proliferation of adipose cell (publication A). The anti-obesity effect of EPA and DHA could be magnified by mild calorie...Tuková tkáň a její hormony hrají nezastupitelnou roli ve fyziologii savců. Při nerovnováze mezi příjmem a výdejem energie dochází k růstu tukové tkáně, a ke změně jejího sekrečního profilu. S obezitou jsou spojována mnohá onemocnění, jako kardiovaskulární onemocnění, dyslipidémie, hypertenze a inzulínová rezistence. n-3 polynenasycené mastné kyseliny s dlouhým řetězcem (LC n-3 PUFAs) z rybích olejů, hlavně eikosapentaenová (EPA) a dokosahexaenová (DHA) kyselina, zlepšují celkový lipidový metabolizmus a brání rozvoji obezity a inzulínové rezistence. Studie, prováděné na myších liniích náchylných k obezitě (C57BL/6), nám poskytují důležité poznatky, týkající se jejich vlivu na savčí tkáně a možného terapeutického využití. Tato disertační práce je založena na pěti publikovaných článcích (A-E). Tři práce se věnovaly problematice bílé tukové tkáně. V těchto pracích jsme ukázali, že bílá tuková tkáň je flexibilní orgán a LC n-3 PUFAs hrají důležitou roli v její biologii. Naše výsledky ukazují, že LC n-3 PUFAs ovlivňují množství tukové tkáně mechanizmy závislými jak na potlačení proliferace, tak i diferenciace tukových buněk (publikace A). Anti-obezitní efekt EPA a DHA může být ještě více umocněn mírnou kalorickou restrikcí (10%). Výsledky z publikace B dokazují, že lipidový katabolizmus a tvorba...Department of Genetics and MicrobiologyKatedra genetiky a mikrobiologieFaculty of SciencePřírodovědecká fakult

Molecular mechanisms affected by n-3 polyunsaturated fatty acids

Adipose tissue and its hormones have an irreplaceable role in the physiology of mammals. The imbalance between energy intake and energy expenditure leads to the expansion of adipose tissue and changes in its secretion profile. With obesity are associated diseases including cardiovascular diseases, dyslipidemia, hypertension and insulin resistance, one of the major public health issues. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) from marine origin, mainly eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids exert numerous beneficial effects, such as improvements of lipid metabolism and prevention of obesity and diabetes. Studies with obesity-prone model mice (C57BL/6) provide us important knowledge regarding their effect on mammalian tissues and to test potential therapeutic interventions. The thesis is based on five published studies (A-E). Three studies are focused on white adipose tissue. In these works we proved that adipose tissue is a flexible organ and LC n- 3 PUFAs are potent regulators of adipose tissue biology. Our results document that LC n- 3 PUFAs affect adipose tissue mass by a mechanism, which depends on counteraction of both, differentiation and proliferation of adipose cell (publication A). The anti-obesity effect of EPA and DHA could be magnified by mild calorie..

Molekulární mechanismy n-3 polynenasycených mastných kyselin

Adipose tissue and its hormones have an irreplaceable role in the physiology of mammals. The imbalance between energy intake and energy expenditure leads to the expansion of adipose tissue and changes in its secretion profile. With obesity are associated diseases including cardiovascular diseases, dyslipidemia, hypertension and insulin resistance, one of the major public health issues. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) from marine origin, mainly eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids exert numerous beneficial effects, such as improvements of lipid metabolism and prevention of obesity and diabetes. Studies with obesity-prone model mice (C57BL/6) provide us important knowledge regarding their effect on mammalian tissues and to test potential therapeutic interventions. The thesis is based on five published studies (A-E). Three studies are focused on white adipose tissue. In these works we proved that adipose tissue is a flexible organ and LC n-3 PUFAs are potent regulators of adipose tissue biology. Our results document that LC n-3 PUFAs affect adipose tissue mass by a mechanism, which depends on counteraction of both, differentiation and proliferation of adipose cell (publication A). The anti-obesity effect of EPA and DHA could be magnified by mild calorie...ÚVOD Tuková tkáň a její hormony hrají nezastupitelnou roli ve fyziologii savců. Při nerovnováze mezi příjmem a výdejem energie dochází k růstu tukové tkáně, a ke změně jejího sekrečního profilu. S obezitou jsou spojována mnohá onemocnění, jako kardiovaskulární onemocnění, dyslipidémie, hypertenze a inzulínová rezistence. n-3 polynenasycené mastné kyseliny s dlouhým řetězcem (LC n-3 PUFAs) z rybích olejů, hlavně eikosapentaenová (EPA) a dokosahexaenová (DHA) kyselina, zlepšují celkový lipidový metabolizmus a brání rozvoji obezity a inzulínové rezistence. Studie, prováděné na myších liniích náchylných k obezitě (C57BL/6), nám poskytují důležité poznatky, týkající se jejich vlivu na savčí tkáně a možného terapeutického využití. Tato disertační práce je založena na pěti publikovaných článcích (A-E). Tři práce se věnovaly problematice bílé tukové tkáně. V těchto pracích jsme ukázali, že bílá tuková tkáň je flexibilní orgán a LC n-3 PUFAs hrají důležitou roli v její biologii. Naše výsledky ukazují, že LC n-3 PUFAs ovlivňují množství tukové tkáně mechanizmy závislými jak na potlačení proliferace, tak i diferenciace tukových buněk (publikace A). Anti-obezitní efekt EPA a DHA může být ještě více umocněn mírnou kalorickou restrikcí (10%). Výsledky z publikace B dokazují, že lipidový katabolizmus a tvorba...Department of Genetics and MicrobiologyKatedra genetiky a mikrobiologieFaculty of SciencePřírodovědecká fakult

Molecular mechanisms affected by n-3 polyunsaturated fatty acids

Adipose tissue and its hormones have an irreplaceable role in the physiology of mammals. The imbalance between energy intake and energy expenditure leads to the expansion of adipose tissue and changes in its secretion profile. With obesity are associated diseases including cardiovascular diseases, dyslipidemia, hypertension and insulin resistance, one of the major public health issues. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) from marine origin, mainly eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids exert numerous beneficial effects, such as improvements of lipid metabolism and prevention of obesity and diabetes. Studies with obesity-prone model mice (C57BL/6) provide us important knowledge regarding their effect on mammalian tissues and to test potential therapeutic interventions. The thesis is based on five published studies (A-E). Three studies are focused on white adipose tissue. In these works we proved that adipose tissue is a flexible organ and LC n-3 PUFAs are potent regulators of adipose tissue biology. Our results document that LC n-3 PUFAs affect adipose tissue mass by a mechanism, which depends on counteraction of both, differentiation and proliferation of adipose cell (publication A). The anti-obesity effect of EPA and DHA could be magnified by mild calorie..

The effect n-3 polyunsaturated fatty acids on gene expression

Katedra buněčné biologieDepartment of Cell BiologyPřírodovědecká fakultaFaculty of Scienc

LTX-315-enabled, radiotherapy-boosted immunotherapeutic control of breast cancer by NK cells

LTX-315 is a nonameric oncolytic peptide in early clinical development for the treatment of solid malignancies. Preclinical and clinical evidence indicates that the anticancer properties of LTX-315 originate not only from its ability to selectively kill cancer cells, but also from its capacity to promote tumortargeting immune responses. Here, we investigated the therapeutic activity and immunological correlates of intratumoral LTX-315 administration in three syngeneic mouse models of breast carcinoma, with a focus on the identification of possible combinatorial partners. We found that breast cancer control by LTX-315 is accompanied by a reconfiguration of the immunological tumor microenvironment that supports the activation of anticancer immunity and can be boosted by radiation therapy. Mechanistically, depletion of natural killer (NK) cells compromised the capacity of LTX-315 to limit local and systemic disease progression in a mouse model of triple-negative breast cancer, and to extend the survival of mice bearing hormone-accelerated, carcinogen-driven endogenous mammary carcinomas. Altogether, our data suggest that LTX-315 controls breast cancer progression by engaging NK cell-dependent immunity