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Abstract Early life stress (ELS) can negatively impact health, increasing the risk of stress-related disorders, such as post-traumatic stress disorder (PTSD). Importantly, PTSD disproportionately affects women, emphasizing the critical need to explore how sex differences influence the genetic and metabolic neurobiological pathways underlying trauma-related behaviors. This study uses the limited bedding and nesting (LBN) paradigm to model ELS and investigate its sex-specific effects on fear memory formation. Employing innovative unsupervised behavioral classification, the current study reveals distinct behavioral patterns associated with fear acquisition and retrieval in male and female mice following ELS. Females exposed to LBN display heightened active fear responses, contrasting with males. Furthermore, the study examined the crucial link between behavioral regulation and cellular metabolism in key brain regions involved in fear and stress processing. Sex-specific and stress-dependent alterations were observed in purine, pyrimidine, and glutamate metabolism within the basolateral amygdala, the dorsal hippocampus, and the ventral hippocampus. These findings provide crucial insights into the complex interplay between metabolic pathways, the neurobiological underpinnings of fear memory, and stress responses. Importantly, they emphasize the significance of considering sex-specific metabolic alterations when investigating stress-related disorders, opening potential avenues for the development of targeted interventions.

Background and objectiveOverweight and obesity affects millions of individuals worldwide and consequently represents a major public health concern. Individuals living with overweight and obesity have difficulty maintaining a low body weight due to known physiological mechanisms which prevent further weight loss and drive weight regain. In contrast, mechanisms which promote low body weight maintenance receive less attention and are largely unknown. To uncover these intrinsic mechanisms, we investigated a human cohort of constitutionally thin (CT) individuals which maintain a low body weight and are resistant to weight gain despite exposure to an obesogenic environment.MethodsTo identify novel genes that contribute to low body weight maintenance, we performed transcriptomics on adipose tissue biopsies collected from CT and normal body weight (NBW) individuals and identified sulfotransferase 1A1 (SULT1A1) as a target for further investigation in mice. Sult1a1 knockout (KO) mice were fed a standard diet to assess the impact of Sult1a1 deletion on metabolic traits. To determine if high-fat feeding recapitulated the CT weight gain resistance phenotype, Sult1a1 KO mice were fed a high-fat diet for 13-weeks. A subset of wild-type and Sult1a1 KO mice from the standard diet were further analyzed for characterization of adipose tissue respiratory capacity.ResultsIn comparison to NBW controls, adipose tissue from CT individuals expresses less SULT1A1. Sult1a1 KO mice weigh 10% less at the end of the study period and on a high-fat diet, Sult1a1 KO mice tended to gain less weight and had reduced fat mass at 14-weeks of age. These changes were associated with reduced fasting insulin and lessened adipose tissue inflammation and fibrosis. Subcutaneous adipose tissue from Sult1a1 KO mice on a standard chow diet had elevated leak respiration, uncoupling protein 1 (UCP1) expression and increased expression of a mitochondrial marker, VDAC, associating Sult1a1 deletion to adipose tissue browning.ConclusionsOur results associate Sult1a1 deletion with a tendency for lower body weight through remodeling of white adipose tissue towards a brown phenotype. The presence of UCP1, the expression of an additional mitochondrial protein and increased respiratory capacity suggest browning of the subcutaneous adipose tissue depot of Sult1a1 KO mice.

Objective: Steroidogenic factor 1 (SF1) expressing neurons in the ventromedial hypothalamus (VMH) have been directly implicated in whole-body metabolism and in the onset of obesity. The co-chaperone FKBP51 is abundantly expressed in the VMH and was recently linked to type 2 diabetes, insulin resistance, adipogenesis, browning of white adipose tissue (WAT) and bodyweight regulation. Methods: We investigated the role of FKBP51 in the VMH by conditional deletion and virus-mediated overexpression of FKBP51 in SF1-positive neurons. Baseline and high fat diet (HFD)-induced metabolic- and stress-related phenotypes in male and female mice were obtained. Results: In contrast to previously reported robust phenotypes of FKBP51 manipulation in the entire mediobasal hypothalamus (MBH), selective deletion or overexpression of FKBP51 in the VMH resulted in only a moderate alteration of HFD-induced bodyweight gain and body composition, independent of sex. Conclusions: Overall, this study shows that animals lacking and overexpressing Fkbp5 in Sf1-expressing cells within the VMH display only a mild metabolic phenotype compared to an MBH-wide manipulation of this gene, suggesting that FKBP51 in SF1 neurons within this hypothalamic nucleus plays a subsidiary role in controlling whole-body metabolism.