Longitudinal sex-specific impacts of high-fat diet on dopaminergic dysregulation and behavior from periadolescence to late adulthood.

OBJECTIVES: Obesity is recognized for its adverse impact on brain health and related behaviors; however, the specific longitudinal effects of a high-fat diet (HFD) from juvenile stages of development through late adulthood remain poorly understood, particularly sex-specific outcomes. This study aimed to determine how prolonged exposure to HFD, commencing during periadolescence, would differentially predispose male and female mice to an elevated risk of dopaminergic dysregulation and associated behavioral deficits. METHODS: One-month-old C57BL/6J male and female mice were subjected to either a control diet or an HFD for 5 and 9 months. Muscle strength, motor skills, sensorimotor integration, and anxiety-like behaviors were assessed at the end of the 5th and 8th months. Key dopaminergic molecules, including dopamine (DA), dopamine receptor D2 (DRD2), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2), were quantified at the end of the 5th or 9th months. RESULTS: Behaviorally, male mice exposed to HFD exhibited more pronounced alterations in sensorimotor integration, anxiety-like behavior, and muscle strength after the 5th month of dietary exposure. In contrast, female mice displayed most behavioral differences after the 8th month of HFD exposure. Physiologically, there were notable sex-specific variations in the dopaminergic pathway response to HFD. Male mice exposed to HFD exhibited elevated tissue levels of VMAT2 and DRD2, whereas female mice showed reduced levels of DRD2 and DAT compared to control groups. DISCUSSION: These findings indicate a general trend of altered time course susceptibility in male mice to chronic HFD consumption compared to their female counterparts, with male mice impacted earlier than females.

High fat diet reveals sex-specific fecal and liver metabolic alterations in C57BL/6J obese mice.

Obesity is a major health concern that poses significant risks for many other diseases, including diabetes, cardiovascular disease, and cancer. Prevalence of these diseases varies by biological sex. This study utilizes a mouse (C57BL/6J) model of obesity to analyze liver and fecal metabolic profiles at various time points of dietary exposure: 5, 9, and 12 months in control or high fat diet (HFD)-exposed mice. Our study discovered that the female HFD group has a more discernable perturbation and set of significant changes in metabolic profiles than the male HFD group. In the female mice, HFD fecal metabolites including pyruvate, aspartate, and glutamate were lower than control diet-exposed mice after both 9th and 12th month exposure time points, while lactate and alanine were significantly downregulated only at the 12th month. Perturbations of liver metabolic profiles were observed in both male and female HFD groups, compared to controls at the 12th month. Overall, the female HFD group showed higher lactate and glutathione levels compared to controls, while the male HFD group showed higher levels of glutamine and taurine compared to controls. These metabolite-based findings in both fecal and liver samples for a diet-induced effect of obesity may help guide future pioneering discoveries relating to the analysis and prevention of obesity in people, especially for females.

Hydrogen peroxide-dependent oxidation of ERK2 within its D-recruitment site alters its substrate selection.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are dysregulated in many pervasive diseases. Recently, we discovered that ERK1/2 is oxidized by signal-generated hydrogen peroxide in various cell types. Since the putative sites of oxidation lie within or near ERK1/2's ligand-binding surfaces, we investigated how oxidation of ERK2 regulates interactions with the model substrates Sub-D and Sub-F. These studies revealed that ERK2 undergoes sulfenylation at C159 on its D-recruitment site surface and that this modification modulates ERK2 activity differentially between substrates. Integrated biochemical, computational, and mutational analyses suggest a plausible mechanism for peroxide-dependent changes in ERK2-substrate interactions. Interestingly, oxidation decreased ERK2's affinity for some D-site ligands while increasing its affinity for others. Finally, oxidation by signal-generated peroxide enhanced ERK1/2's ability to phosphorylate ribosomal S6 kinase A1 (RSK1) in HeLa cells. Together, these studies lay the foundation for examining crosstalk between redox- and phosphorylation-dependent signaling at the level of kinase-substrate selection.

High-Fat Diet-Induced Weight Gain, Behavioral Deficits, and Dopamine Changes in Young C57BL/6J Mice.

Chronic exposure to a high-fat diet (HFD) may predispose individuals to neuropathologies and behavioral deficits. The objective of this study was to determine the temporal effects of a HFD on weight gain, behavioral deficits, and dopamine changes in young mice. One-month old C57BL/6J male and female mice were fed either a control diet (containing 10% calories from fat) or a HFD (containing 45% of calories from fat) for 5 months. Physiological measures such as food consumption, body weight, blood glucose, and behaviors such as motor activity, sensorimotor integration, and anxiety-like behaviors were evaluated monthly. Dopamine (DA), dopamine receptor D2 (DRD2), and dopamine transporter (DT) protein expression levels were measured in the midbrain after 5 months of dietary exposure. Results showed that body weight was significantly greater in the HFD-exposed group compared to the control-group at the end of the 4th month, while food consumption was similar in both groups. For behavioral effects, the HFD group exhibited a significant decrease in motor activity in the open field test after 3 months, and rearing frequency after 4 months of dietary exposure. The HFD group also showed deficits in sensorimotor integration after 3 months. Specifically, chronic HFD exposure increased contact time and time to remove the first adhesive tape in the adhesive-tape removal test (p < 0.05). Furthermore, the HFD group showed significant deficits in balance/coordination compared to the control group after 4 months of dietary exposure using the beam traverse test, and increased anxiety-like behavior tested by both the open field and light/dark box tests (p < 0.05). Neurochemical measurements showed that HFD-exposed mice had significantly higher midbrain DA and DRD2 protein levels compared to the control group after 5 months of dietary exposure (p < 0.05). These results indicate that the impact of HFD on the C57BL/6J mouse strain began at the 3rd month of dietary exposure. Behavioral deficits occurred at a similar time point as increased body weight, at about 3-4 months. Overall, this study provides a critical understanding on how HFD-induced changes in weight gain and behavioral deficits in this strain occur over time. The behavioral changes support the idea that changes also occurred in neurochemical pathways such as dopamine dysregulation.