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Short-Term High-Fat Diet Increases Leptin Activation of CART Neurons and Advances Puberty in Female Mice.

ABSTRACT: Leptin is a permissive factor for puberty initiation, participating as a metabolic cue in the activation of the kisspeptin (Kiss1)-gonadotropin-releasing hormone neuronal circuitry; however, it has no direct effect on Kiss1 neurons. Leptin acts on hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons, participating in the regulation of energy homeostasis. We investigated the influence of a short-term high-fat diet (HFD) on the effect of leptin on puberty timing. Kiss1-hrGFP female mice received a HFD or regular diet (RD) after weaning at postnatal day (PN)21 and were studied at PN28 and PN32. The HFD increased body weight and plasma leptin concentrations and decreased the age at vaginal opening (HFD, 32 ± 0.53 days; RD, 38 ± 0.67 days). Similar colocalization of neurokinin B and dynorphin in Kiss1-hrGFP neurons of the arcuate nucleus (ARC) was observed between the HFD and RD groups. The HFD increased CART expression in the ARC and Kiss1 messenger RNA expression in the anteroventral periventricular (AVPV)/anterior periventricular (Pe). The HFD also increased the number of ARC CART neurons expressing leptin-induced phosphorylated STAT3 (signal transducer and activator of transcription 3) at PN32. Close apposition of CART fibers to Kiss1-hrGFP neurons was observed in the ARC of both RD- and HFD-fed mice. In conclusion, these data reinforce the notion that a HFD increases kisspeptin expression in the AVPV/Pe and advances puberty initiation. Furthermore, we have demonstrated that the HFD-induced earlier puberty is associated with an increase in CART expression in the ARC. Therefore, these data indicate that CART neurons in the ARC can mediate the effect of leptin on Kiss1 neurons in early puberty induced by a HFD.

SUBMITTER: Venancio JC

PROVIDER: S-EPMC5695829 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Short-Term High-Fat Diet Increases Leptin Activation of CART Neurons and Advances Puberty in Female Mice.

Venancio Jade Cabestre JC Margatho Lisandra Oliveira LO Rorato Rodrigo R Rosales Roberta Ribeiro Costa RRC Debarba Lucas Kniess LK Coletti Ricardo R Antunes-Rodrigues Jose J Elias Carol F CF Elias Lucila Leico K LLK

Endocrinology 20171101 11

Leptin is a permissive factor for puberty initiation, participating as a metabolic cue in the activation of the kisspeptin (Kiss1)-gonadotropin-releasing hormone neuronal circuitry; however, it has no direct effect on Kiss1 neurons. Leptin acts on hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons, participating in the regulation of energy homeostasis. We investigated the influence of a short-term high-fat diet (HFD) on the effect of leptin on puberty timing. Kiss1-hrGFP f ...[more]

PMID: 28938405

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Project description:Background/objectivesRecent findings have highlighted the detrimental influence of maternal overnutrition and obesity on fetal development and early life development. However, there are no evidence-based guidelines regarding the optimal strategy for dietary intervention before pregnancy.Subjects/methodsWe used a murine model to study whether switching from a high-fat (HF) diet to a normal-fat (NF) diet (H1N group) 1 week before pregnancy could lead to in utero reprogramming of female offspring obesity; comparator groups were offspring given a consistent maternal HF group or NF group until weaning. After weaning, all female offspring were given the HF diet for either 9 or 12 weeks before being killed humanely.ResultsH1N treatment did not result in maternal weight loss before pregnancy. NF offsprings were neither obese nor glucose intolerant during the entire experimental period. H1N offsprings were most obese after the 12-week postweaning HF diet and displayed glucose intolerance earlier than HF offsprings. Our mechanistic study showed reduced adipocyte insulin receptor substrate 1 (IRS1) and hepatic IRS2 expression and increased adipocyte p-Ser(636/639) and p-Ser(612) of H1N or HF offspring compared with that in the NF offspring. Among all groups, the H1N offspring had lowest level of IRS1 and the highest levels of p-Ser(636/639) and p-Ser(612) in gonadal adipocyte. In addition, the H1N offspring further reduced the expression of Glut4 and Glut2, vs those of the HF offspring, which was lower compared with the NF offspring. There were also enhanced expression of genes inhibiting glycogenesis and decreased hepatic glycogen in H1N vs HF or NF offspring. Furthermore, we showed extremely higher expression of lipogenesis and adipogenesis genes in gonadal adipocytes of H1N offspring compared with all other groups.ConclusionsOur results suggest that a transition from an HF diet to an NF diet shortly before pregnancy, without resulting in maternal weight loss, is not necessarily beneficial and may have deleterious effects on offspring.

Project description:The aim of this study was to explore the effect of short-chain inulin on cecal microbiota of high-fat diet-fed leptin knockout mice and the different influences of cecal microbiota on wild-type and leptin knockout mice. A total of 18 specific pathogen-free male C57BL/6J wild-type mice and 18 C57BL/6J leptin knockout mice (OB/OB mice) were selected. Mice were divided into six groups according to their genotype: wild-type mice have three groups, including the normal diet group (CT), 60% high-fat diet group (CH), and 60% high fat with 10% short-chain inulin group (CHI); OB/OB mice were also divided into three groups, including the normal diet group (OT), 60% high-fat diet group (OH), and 60% high fat with 10% short-inulin group (OHI). The mice were fed for 8 weeks to analyze the diversity of cecal microbiota. The results show that compared with CH and OH, the variety of cecal microbiota was significantly reduced in CH and OH and further reduced in CHI and OHI. Bifidobacterium and Lactobacillus are the biomarkers in genus level. Dietary short-chain inulin significantly enhanced Bifidobacterium in OHI compared with OH (p < 0.01) and significantly reduced in CHI and compared with CH (p < 0.01). Lactobacillus was significantly enhanced in CHI and OHI compared with CH and OH, respectively (p < 0.01). Blautia was significantly enhanced in CH and OH compared with other groups (p < 0.01). Both Escherichia-Shigella and Enterococcus were significantly reduced in CHI and OHI, compared with CH and OH, respectively (p < 0.05). Escherichia-Shigella was even lower than CT and OT in CHI and OHI. Functional prediction of microbial communities showed that the abundance of amino acid sugar and nucleotide sugar metabolism pathways were significantly enhanced (p < 0.05) in CH and OH, and OH was significantly higher than CH (p < 0.05). Among the leptin knockout groups, PICRUSt2 function prediction showed that the fatty acid metabolism pathway significantly reduced (p < 0.05) in OHI and OT compared with OH. In conclusion, short-chain inulin modulated the dysbiosis induced by high-fat diet, improved probiotics growth and inhibited conditioned pathogenic bacteria, and the influences were significantly different in wild-type and leptin knockout mice.

Project description:BackgroundA westernized diet comprising a high caloric intake from animal fats is known to influence the development of pathological inflammatory conditions. However, there has been relatively little focus upon the implications of such diets for the progression of infectious disease. Here, we investigated the influence of a high-fat (HF) diet upon parameters that influence Listeria monocytogenes infection in mice.ResultsWe determined that short-term administration of a HF diet increases the number of goblet cells, a known binding site for the pathogen, in the gut and also induces profound changes to the microbiota and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to oral L. monocytogenes infection in mice fed a HF diet relative to low fat (LF)- or chow-fed animals. Prior to Listeria infection, short-term consumption of HF diet elevated levels of Firmicutes including Coprococcus, Butyricicoccus, Turicibacter and Clostridium XIVa species. During active infection with L. monocytogenes, microbiota changes were further exaggerated but host inflammatory responses were significantly downregulated relative to Listeria-infected LF- or chow-fed groups, suggestive of a profound tempering of the host response influenced by infection in the context of a HF diet. The effects of diet were seen beyond the gut, as a HF diet also increased the sensitivity of mice to systemic infection and altered gene expression profiles in the liver.ConclusionsWe adopted a systems approach to identify the effects of HF diet upon L. monocytogenes infection through analysis of host responses and microbiota changes (both pre- and post-infection). Overall, the results indicate that short-term consumption of a westernized diet has the capacity to significantly alter host susceptibility to L. monocytogenes infection concomitant with changes to the host physiological landscape. The findings suggest that diet should be a consideration when developing models that reflect human infectious disease.

Project description:IntroductionIncreased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk. In this study, we identified the effects of peripubertal exposure to HFD and investigated its mechanism of enhancing tumorigenesis.MethodsThree-week-old BALB/c mice fed a low-fat diet (LFD) or HFD were subjected to 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis. At 9 weeks of age, half the mice on LFD were switched to HFD (LFD-HFD group) and half the mice on HFD were switched to LFD (HFD-LFD group). Tumor gene expression was evaluated in association with diet and tumor latency.ResultsThe peripubertal HFD reduced the latency of DMBA-induced mammary tumors and was associated with tumor characteristics similar to those in mice fed a continuous HFD. Notably, short-latency tumors in both groups shared gene expression characteristics and were more likely to have adenosquamous histology. Both HFD-LFD and continuous HFD tumors showed similar gene expression patterns and early latency. Adult switch from HFD to LFD did not reverse peripubertal HFD tumor promotion. Increased proliferation, hyperplasia, and macrophages were present in mammary glands before tumor development, implicating these as possible effectors of tumor promotion. Despite a significant interaction between pubertal diet and carcinogens in tumor promotion, peripubertal HFD by itself produced persistent macrophage recruitment to mammary glands.ConclusionsIn obesity-resistant mice, peripubertal HFD is sufficient to irreversibly promote carcinogen-induced tumorigenesis. Increased macrophage recruitment is likely a contributing factor. These results underscore the importance of early life exposures to increased adult cancer risk and are consistent with findings that an HFD in normal weight premenopausal women leads to increased breast cancer risk. Notably, short-latency tumors occurring after peripubertal HFD had characteristics similar to human basal-like breast cancers that predominantly develop in younger women.

Dataset Information

Short-Term High-Fat Diet Increases Leptin Activation of CART Neurons and Advances Puberty in Female Mice.

Publications

Short-Term High-Fat Diet Increases Leptin Activation of CART Neurons and Advances Puberty in Female Mice.

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