Early life stress exacerbates obesity in adult female mice via mineralocorticoid receptor-dependent increases in adipocyte triglyceride and glycerol content.

Previously, we have shown that Maternal Separation and Early Weaning (MSEW) exacerbates high fat diet (HF)-induced visceral obesity in female offspring compared to normally reared female mice. Stress hormones such as glucocorticoids and mineralocorticoids are critical mediators in the process of fat expansion, and both can activate the mineralocorticoid receptor (MR) in the adipocyte. Therefore, this study aimed to, comprehend the specific effects of MSEW on adipose tissue basic homeostatic function, and investigate whether female MSEW mice show an exacerbated obesogenic response mediated by MR. Gonadal white adipose tissue (gWAT), a type of visceral fat, was collected to assess lipidomics, transcriptomics, and in vitro lipolysis assay. Obese female MSEW mice showed increased adiposity, elevated 44:2/FA 18:2 + NH4 lipid class and reduced mitochondrial DNA density compared to obese control counterparts. In addition, single-cell RNA sequencing in isolated pre- and mature adipocytes showed a ~9-fold downregulation of aquaglycerolporin 3 (Aqp3), a channel responsible for glycerol efflux in adipocytes. Obese MSEW mice showed high levels of circulating aldosterone and gWAT-derived corticosterone compared to controls. Further, the MR blocker spironolactone (Spiro, 100 mg/kg/day, 2 weeks) normalized the elevated intracellular glycerol levels, the greater in vitro lipolysis response, and the number of large size adipocytes in MSEW mice compared to the controls. Our data suggests that MR plays a role promoting adipocyte hypertrophy in female MSEW mice by preventing lipolysis via glycerol release in favor of triglyceride formation and storage.

Sex and race define the effects of adverse childhood experiences on self-reported BMI and metabolic health biomarkers.

BACKGROUND: Adverse childhood experiences (ACEs) are an independent risk factor for chronic diseases, including type 2 diabetes, stroke and ischemic heart disease. However, the effect of ACEs considering sex and race are not often reported in cohorts showing multiracial composition, with power to evaluate effects on underrepresented populations. AIM: To determine how sex and race affected the association of combined and individual ACEs with metabolic health biomarkers in the Southern Community Cohort Study (2012-2015). METHODS: Self-reported data were analyzed from ACE surveys performed during the second follow-up of a cohort comprised by over 60% of Black subjects and with an overall mean age of 60 years. RESULTS: BMI steadily increased with cumulative ACEs among Black and White women, but remained relatively stable in White men with ≥ 4 ACEs. Contrary, Black men showed an inverse association between ACE and BMI. Secondary analysis of metabolic outcomes showed that physical abuse was correlated with a 4.85 cm increase in waist circumference in Black subjects. Total cholesterol increased among individuals with more than 4 ACEs. In addition, increases in HbA1c were associated with emotional and maternal abuse in Black women and sexual abuse in White women. CONCLUSIONS: BMI is strongly associated with cumulative ACEs in women regardless the race, while waist circumference is strongly associated with ACEs in Black individuals, which combined with reduced BMI may indicate increased central adiposity in Black men. Our study suggests that sex and race influence the contribution of certain ACEs to impair metabolic health.

Epididymal Fat-Derived Sympathoexcitatory Signals Exacerbate Neurogenic Hypertension in Obese Male Mice Exposed to Early Life Stress.

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Untargeted Stable Isotope Probing of the Gut Microbiota Metabolome Using 13C-Labeled Dietary Fibers.

The gut microbiome generates numerous metabolites that exert local effects and enter the circulation to affect the functions of many organs. Despite extensive sequencing-based characterization of the gut microbiome, there remains a lack of understanding of microbial metabolism. Here, we developed an untargeted stable isotope-resolved metabolomics (SIRM) approach for the holistic study of gut microbial metabolites. Viable microbial cells were extracted from fresh mice feces and incubated anaerobically with 13C-labeled dietary fibers including inulin or cellulose. High-resolution mass spectrometry was used to monitor 13C enrichment in metabolites associated with glycolysis, the Krebs cycle, the pentose phosphate pathway, nucleotide synthesis, and pyruvate catabolism in both microbial cells and the culture medium. We observed the differential use of inulin and cellulose as substrates for biosynthesis of essential and non-essential amino acids, neurotransmitters, vitamin B5, and other coenzymes. Specifically, the use of inulin for these biosynthetic pathways was markedly more efficient than the use of cellulose, reflecting distinct metabolic pathways of dietary fibers in the gut microbiome, which could be related with host effects. This technology facilitates deeper and holistic insights into the metabolic function of the gut microbiome (Metabolomic Workbench Study ID: ST001651).

Exacerbated obesogenic response in female mice exposed to early life stress is linked to fat depot-specific upregulation of leptin protein expression.

Early life stress (ELS) is an independent risk factor for increased BMI and cardiometabolic disease risk later in life. We have previously shown that a mouse model of ELS, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. Therefore, the aim of this study was to investigate 1) whether the short- and long-term effects of HF on leptin expression are influenced by MSEW in a sex-specific manner and 2) the potential epigenetic mechanisms underlying the MSEW-induced changes in leptin expression. After 1 wk of HF, both MSEW male and female mice displayed increased fat mass compared with controls (P < 0.05). However, only MSEW female mice showed elevated leptin mRNA expression in gonadal white adipose tissue (gWAT; P < 0.05). After 12 wk of HF, fat mass remained increased only in female mice (P < 0.05). Moreover, plasma leptin and both leptin mRNA and protein expression in gWAT were augmented in MSEW female mice compered to controls (P < 0.05), but not in MSEW male mice. This association was not present in subcutaneous WAT. Furthermore, among 16 CpG sites in the leptin promoter, we identified three hypomethylated sites in tissue from HF-fed MSEW female mice compared with controls (3, 15, and 16, P < 0.05). These hypomethylated sites showed greater binding of key adipogenic factors such as PPARγ (P < 0.05). Taken together, our study reveals that MSEW superimposed to HF increases leptin protein expression in a sex- and fat depot-specific fashion. Our data suggest that the mechanism by which MSEW increases leptin expression could be epigenetic.

Sensory signals mediating high blood pressure via sympathetic activation: role of adipose afferent reflex.

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Although there are numerous reviews focused on the role of sympathetic nerves in different models of hypertension, few have revised the contribution of afferent nerves innervating adipose tissue and their role in the development of obesity-induced hypertension. Both clinical and basic research support the beneficial effects of bilateral renal denervation in lowering blood pressure. However, recent studies revealed that afferent signals from adipose tissue, in an adipose-brain-peripheral pathway, could contribute to the increased sympathetic activation and blood pressure during obesity. This review focuses on the role of adipose tissue afferent reflexes and briefly describes a number of other afferent reflexes modulating blood pressure. A comprehensive understanding of how multiple afferent reflexes contribute to the pathophysiology of essential and/or obesity-induced hypertension may provide significant insights into improving antihypertensive therapeutic approaches.

Female Mice Exposed to Postnatal Neglect Display Angiotensin II-Dependent Obesity-Induced Hypertension.

Background We have previously reported that female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, show exacerbated diet-induced obesity associated with hypertension. The goal of this study was to test whether MSEW promotes angiotensin II-dependent hypertension via activation of the renin-angiotensin system in adipose tissue. Methods and Results MSEW was achieved by daily separations from the dam and weaning at postnatal day 17, while normally reared controls were weaned at postnatal day 21. Female controls and MSEW weanlings were placed on a low-fat diet (LF, 10% kcal from fat) or high-fat diet (HF, 60% kcal from fat) for 20 weeks. MSEW did not change mean arterial pressure in LF-fed mice but increased it in HF-fed mice compared with controls (P<0.05). In MSEW mice fed a HF, angiotensin II concentration in plasma and adipose tissue was elevated compared with controls (P<0.05). In addition, angiotensinogen concentration was increased solely in adipose tissue from MSEW mice (P<0.05), while angiotensin-converting enzyme protein expression and activity were similar between groups. Chronic enalapril treatment (2.5 mg/kg per day, drinking water, 7 days) reduced mean arterial pressure in both groups of mice fed a HF (P<0.05) and abolished the differences due to MSEW. Acute angiotensin II-induced increases in mean arterial pressure (10 µg/kg SC) were attenuated in untreated MSEW HF-fed mice compared to controls (P<0.05); however, this response was similar between groups in enalapril-treated mice. Conclusions The upregulation of angiotensinogen and angiotensin II in adipose tissue could be an important mechanism by which female MSEW mice fed a HF develop hypertension.