Biology subjects

Morris, E. M.

Publications and source records attributed to Morris, E. M..

6 recordsLinked to original sources

bioRxiv2026

Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement

Ketogenesis and ketone body metabolism are linked to brain health benefits, including delaying age-related cognitive decline and neurodegeneration. Exercise, particularly when combined with an overnight fast, stimulates ketogenesis and ketone body turnover as well as improves brain metabolism and cognition. Yet, whether ketone metabolism is obligatory for this response is unknown. Here, we use chronic exercise via voluntary wheel running plus time-restricted feeding (VWR+TRF, fasting from ZT10.5-18.5) to explore whether ketone bodies are a potential mediator of exercise-induced brain health benefits in middle-aged mice. To independently distinguish the roles of neuronal ketone body metabolism vs. hepatic ketone body production, we studied middle-age female neuronal-specific SCOT knockout mice and female hepatocyte-specific HMGCS2 knockout mice, respectively. VWR+TRF was compared to sedentary ad-libitum fed (SED+AL) mice to assess the impact on whole-body metabolism (indirect calorimetry), cognition (Barnes Maze and Y-Maze), and molecular adaptations in the hippocampus (proteomics). VWR+TRF robustly upregulated systemic lipid oxidation in all mice, regardless of genotype, during the first 6.5 hours of the dark period. In female SCOT-Neuron-KO mice, we show impaired responses to VWR+TRF in indices of short- and long-term memory. Proteomic analysis of isolated hippocampi revealed that SCOT-Neuron-KO mice failed to globally upregulate key facilitators of synaptic function, including leucine-rich repeated transmembrane proteins, neurexins, and neuroligins. In female HMGCS2-Liver-KO mice, impaired responses to VWR+TRF in indices of short-term memory were paired with an upregulation in ketogenesis machinery in the hippocampal proteome, suggesting potential in vivo evidence of cerebral ketogenesis, a mechanism mitigating an otherwise more pronounced behavioral phenotype. Together, these findings suggest that neuronal ketone body utilization is essential, and hepatic ketone production is contributory, to the full cognitive and synaptic adaptations to exercise plus time-restricted feeding, supporting ketone metabolism as a key mechanistic link between metabolic state and brain health in midlife.

physiology↗

bioRxiv2024

Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting

ObjectiveThe capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within-meal food intake inhibition is impaired in human subjects with obesity and obese pre-clinical models. Previously, we have shown decreased hepatic mitochondrial energy metabolism (i.e., oxidative metabolism & ADP-dependent respiration) in male liver-specific, heterozygous PGC1a mice results in increased short-term diet-induced weight gain with increased within meal food intake. Herein, we tested the hypothesis that decreased liver mitochondrial energy metabolism impairs meal termination following nutrient oral pre-loads. MethodsLiver mitochondrial respiratory response to changes in {Delta}GATP and adenine nucleotide concentration following fasting were examined in male liver-specific, heterozygous PGC1a mice. Further, food intake and feeding behavior during basal conditions, following nutrient oral pre-loads, and following fasting were investigated. ResultsWe observed male liver-specific, heterozygous PGC1a mice have reduced mitochondrial response to changes in {Delta}GATP and tissue ATP following fasting. These impairments in liver energy state are associated with larger and longer meals during chow feeding, impaired dose-dependent food intake inhibition in response to mixed and individual nutrient oral pre-loads, and greater acute fasting-induced food intake. ConclusionThese data support previous work proposing liver-mediated food intake regulation through modulation of peripheral satiation signals.

physiology↗

bioRxiv2023

VCD-induced menopause mouse model reveals reprogramming of hepatic metabolism

Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype. In this study, we treated female C57BL6/J mice with VCD (160mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions. VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS diet resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways. Our findings suggest that the VCD- induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.

physiology↗

bioRxiv2022

Early life stress exposure increases susceptibility to high fat/high sucrose diet in female mice

Exposure to stress early in life has been associated with adult-onset co-morbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early life stress and consumption of a western style diet contribute to the development of obesity, however, relatively few pre-clinical studies have been performed in female rodents, which are known to be protected against diet induced obesity and metabolic dysfunction. In this study we gave naive and NMS female mice access to a high-fat/high-sucrose (HFS) diet beginning at 4 weeks of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 weeks on the diet, driven partly by increased food intake. Female NMS mice on a HFS diet showed widespread mechanical hypersensitivity compared to either naive mice on a HFS diet or NMS mice on a control diet. HFS diet-fed NMS mice also had impaired glucose tolerance and fasting hyperinsulinemia. Strikingly, female NMS mice on a HFS diet showed evidence of hepatic steatosis with increased triglyceride levels and altered glucocorticoid receptor levels and phosphorylation state. They also exhibited increased energy expenditure as observed via indirect calorimetry and expression of pro-inflammatory markers in perigonadal adipose. Altogether, our data suggest that early life stress exposure increased the susceptibility of female mice to develop diet-induced metabolic dysfunction and pain-like behaviors.

physiology↗

bioRxiv2020

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-induced Weight Gain in Male Mice

Central integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previous work described increased acute food intake following chemical reduction of hepatic fatty acid oxidation and ATP levels, which was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a liver-specific PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male mice have 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain and 35% greater positive energy balance compared to wildtype (WT) (p<0.05). The greater energy balance was associated with altered feeding behavior and lower activity energy expenditure during HFHS in LPGC1a males. Importantly, no differences in HFHS-induced weight gain or energy metabolism was observed between female WT and LPGC1a mice. WT and LPGC1a mice underwent sham or HBV to assess whether vagal signaling was involved in HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p<0.05) in male WT, but not LPGC1a mice. As above, sham LPGC1a males gain 70% more weight during short-term HFHS feeding than sham WT (p<0.05). These data demonstrate a sexspecific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need of more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain. Key Points SummaryO_LIReduced liver PGC1a expression results in reduced mitochondrial fatty acid oxidation and respiratory capacity in male mice. C_LIO_LIMale mice with reduced liver PGC1a expression (LPGC1a) demonstrate greater short-term high-fat/high-sucrose diet-induced weight gain compared to wildtype. C_LIO_LIGreater positive energy balance during HFHS feeding in male LPGC1a mice is associated with altered food intake patterns and reduced activity energy expenditure. C_LIO_LIFemale LPGC1a mice do not have differences in short-term HFHS-induced body weight gain or energy metabolism compared to wildtype. C_LIO_LIDisruption of vagal signaling through common hepatic branch vagotomy increases short-term HFHS-induced weight gain in male wildtype mice, but does not alter male LPGC1a weight gain. C_LI

physiology↗

bioRxiv2018

Hepatocyte-Specific Hepatocyte Nuclear Factor 4 alpha (HNF4α) Deletion Decreases Resting Energy Expenditure By Disrupting Lipid and Carbohydrate Homeostasis

Hepatocyte Nuclear Factor 4 alpha (HNF4) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4 in metabolism, its overall role in whole body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4 deletion (HNF4-KO) in mice on whole body energy expenditure (EE) and substrate utilization in fed, fasted, and high fat diet (HFD) conditions. HNF4-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4-KO mice were able to upregulate lipid oxidation during HFD suggesting that their metabolic flexibility was intact. However, only hepatocyte specific HNF4-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic {beta}-oxidation in HNF4-KO livers across all feeding conditions. Together, our data suggest deletion of hepatic HNF4 increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole body energy expenditure. These data clarify the role of hepatic HNF4 on systemic metabolism and energy homeostasis.

physiology↗