Sex-specific lipid molecular signatures in obesity-associated metabolic dysfunctions revealed by lipidomic characterization in ob/ob mouse

González‐Granillo, Marcela; Helguero, Luísa A.; Alves, Eliana; Archer, Amena; Savva, Christina; Pedrelli, Matteo; Osman, Ahmed; Li, Xidan; Domingues, M. Rosário M.; Parini, Paolo; Gustafsson, Jan‐Åke; Korach-André, Marion

doi:10.1186/s13293-019-0225-y

Cited by 31 publications

(38 citation statements)

References 59 publications

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“…S1A). However, as also noted previously (33), the fat distribution was sex dependent. Males had more visceral white adipose tissue (VAT) and less subcutaneous white adipose tissue (SAT) in relation to total fat (Suppl.…”

Section: Base-line Colon Transcriptome and Sex Differencessupporting

confidence: 83%

“…1B). These results support previous observations that obese males are more susceptible to glucose intolerance and insulin resistance than females (33,34). Next, in order to detail the impact of HFD on the colon, we compared the RNA-Seq data of distal colon samples for both male and female mice fed CD with those fed HFD.…”

Section: Sex Differences In High-fat Diet-fed Micesupporting

confidence: 82%

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High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

Hases

Archer

Indukuri

et al. 2020

Preprint

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These authors contributed equally to the work. AbstractEpidemiological studies highlight a strong association between obesity and colorectal cancer (CRC), especially in men. Estrogen, on the other hand, is associated with protection against both the metabolic syndrome and CRC. The colon is the first organ to respond to a high-fat diet (HFD), and estrogen receptor beta (ERβ) in the intestine appears to prevent CRC. How estrogen impacts the colon under HFD condition has, however, not been investigated. Estrogen can act through three different receptors (ERα, ERβ, GPER1) which all may impact metabolism. In an effort to dissect this, we fed mice a control diet or a high-fat diet (HFD) for 13 weeks and administered receptor-selective estrogenic ligands for the last three weeks. We recorded corresponding physiological impact on fat distribution, fasting glucose, colon crypt proliferation and immune cell infiltration, and the colon transcriptome response. We identify clear sex-differences at the transcriptome level, both at base line and after HFD and ligand treatments. An unexpected observation was the significant sex-differences and impact by HFD and estrogens on circadian clock gene expression, such as Npas2 and Arntl (Bmal1), in the colon. Both sexes also exhibited an increased infiltration of F4/80+ macrophages as a result of HFD. In males, but not females, this was accompanied by changes in colonic epithelial cell proliferation. ERα-selective PPT treatment had significant systemic effects, reducing body weight in both sexes, whereas ERβ-selective DPN treatment did not impact body weight, but reduced infiltration of F4/80+ macrophages in colon of both sexes and attenuated HFD-induced proliferation of male colon crypts. Both ERα and ERβ activation contributed to circadian clock gene regulations. We detail for the first time how HFD and estrogens modulate the colon transcriptome and physiology in a sex and ER-specific manner.

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Section: Base-line Colon Transcriptome and Sex Differencessupporting

confidence: 83%

Section: Sex Differences In High-fat Diet-fed Micesupporting

confidence: 82%

High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

Hases

Archer

Indukuri

et al. 2020

Preprint

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“…Indeed, Gonzàlez‐Granilo et al, performing an innovative lipidomic and trascriptomic study, observed a qualitative difference in lipid content of hepatocytes in male and female mice, associated with a different expression of elongation and desaturation enzymes. As a result, hepatocytes in male mice seem to have a lower content of unsaturated fatty acids, with a prominent lack of monounsaturated fatty acids and a higher content of PUFAs 28 . Although the latter result is partially conflicting with previous conceptions, the altogether of evidence suggests that endocrine differences between sexes may influence the process of de novo lipogenesis and, potentially, the mechanism of lipotoxicity.…”

Section: Metabolic Pro‐inflammatory Signals: Potential Triggers Of Nafldmentioning

confidence: 85%

Macrophages in the pathophysiology of NAFLD: The role of sex differences

Ministrini

Montecucco

Sahebkar

et al. 2020

Eur J Clin Investigation

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Nonalcoholic fatty liver disease (NAFLD) is a multifactorial pathological condition, which recognizes a certain sexual dimorphism. Experimental and clinical studies provided evidence for a critical role of macrophages in NAFLD development and progression. Especially, liver-resident macrophages (also known as Kupffer cells) are likely the common final pathway of several pro-steatosic signals. A huge amount of danger-associated molecular patterns recognized by Kupffer cells is provided within the liver by lipid and glucose toxicity. Other pro-inflammatory signals come from surrounding tissues into the portal vein, directly to the liver: they come from dysfunctional adipocytes, adipose tissue macrophages and gut dysbiosis. These complex crosstalks are differently represented across sexes, as sexual hormones control many of these processes. Sexual dimorphism then modulates metabolic and inflammatory cascades driving the liver from a simple steatosis to NAFLD and beyond.Here, metabolic and inflammatory mechanisms underlying NALFD pathophysiology will be updated. A special attention will be paid to describe sex-related differences that could provide insights for patient stratification and more tailored therapeutic approaches. K E Y W O R D Sinflammation, Kupffer cells, macrophages, microbiome, nonalcoholic fatty live disease 2 of 9 | MINISTRINI eT al.

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“…Men and postmenopausal women, in general, have less total body fat and a higher accumulation of visceral adipose tissue (VAT) characterized as the "male, apple shape fat distribution phenotype". Premenopausal women accumulate more gluteal and subcutaneous adipose tissue (SAT) characterized as the "female, pear shape fat distribution phenotype" [16][17][18][19][20]. The decreased circulating hormones in postmenopausal women may explain the increased visceral obesity that is highly correlated with metabolic complications.…”

Section: Erβ In Visceral and Subcutaneous Adipose Tissuementioning

confidence: 99%

“…In a recent study, we showed that sex-specific fatty acid and triglyceride (TG) pathways exist in both adipose depot VAT and SAT in ob/ob mouse fed a control diet [20], with males synthetizing more C18:2n-6 trans fatty acid associated with inflammation, and more of the long-chain TGs in VAT compared to females. These differences could be the consequence of the different genetic basis of fat distribution between the sexes [29].…”

Section: Erβ In Visceral and Subcutaneous Adipose Tissuementioning

confidence: 99%