Biology subjects

McCoin, C. S.

Publications and source records attributed to McCoin, C. S..

4 recordsLinked to original sources

bioRxiv2026

Brca1 heterozygosity leads to hepatic steatosis in male and female mice despite sexually dimorphic effects on systemic metabolism

Carrying a germline mutation in BRCA1 is associated with an increased risk of several cancers, including breast and ovarian. Our recent work has demonstrated that obesity is associated with elevated levels of DNA damage in breast glands in this high-risk population. BRCA1 is a canonical tumor suppressor gene primarily recognized for its role in DNA damage repair, yet emerging evidence suggests broader functions in metabolic regulation. To determine whether heterozygous loss of Brca1, as seen in individuals who carry a germline mutation, modifies susceptibility to diet-induced metabolic dysfunction in a sex-dependent manner, we subjected wild-type (WT) and Brca1+/- mice of both sexes to a high-fat diet (HFD) and performed longitudinal metabolic phenotyping. Female Brca1+/- mice exhibited pronounced obesity, increased adiposity, hyperinsulinemia, and impaired glucose tolerance. In contrast, male Brca1+/- mice showed modest resistance to HFD-induced weight gain and displayed improved glucose tolerance compared to WT controls. Notably, Brca1 heterozygosity led to more severe hepatic steatosis with HFD, indicating a shared susceptibility to liver lipid accumulation despite divergent systemic outcomes. In females, steatosis was associated with reduced mitochondrial respiratory complex IV activity and transcriptional remodeling that favored lipid storage. Treatment with the dual GLP1/GIP receptor agonist tirzepatide ameliorated systemic metabolic dysfunction and hepatic steatosis in HFD-fed female Brca1+/- mice. These findings identify Brca1 heterozygosity as a modifier of metabolic disease risk, expanding BRCA1 biology beyond tumor suppression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/708005v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@17f9592org.highwire.dtl.DTLVardef@134c2c2org.highwire.dtl.DTLVardef@de69d8org.highwire.dtl.DTLVardef@1f6f1af_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2026

Hepatocyte Estrogen Receptor α Mediates Estrogen-induced Augmentation of Hepatic 1 Mitochondrial Respiration Following Ovariectomy.

Whole-body estrogen receptor (ER) knockout mice develop hepatic steatosis; however, liver-specific ER knockout (LERKO) mice fail to recapitulate this susceptibility and maintain normal hepatic mitochondrial function. However, estrogen-mediated protection against hepatic steatosis is lost in LERKO mice following ovariectomy (OVX). Here, we tested whether loss of hepatic ER blunts estrogen modulation of hepatic mitochondrial respiratory capacity and mitochondrial proteome following ovariectomy (OVX). Sham or ovariectomy (OVX) surgery was performed in middle-aged female mice (36-40 weeks), followed by AAV injection to generate Control (Con; GFP) or LERKO mice (Cre). All mice were placed on a high-fat diet (HFD) for 10 weeks following surgery. Half of the OVX mice received 17-beta estradiol (E2) replacement (OVX+E2) for the last 4 weeks of HFD. OVX mice had greater body mass and adiposity, which was reversed by E2 replacement in both Con and LERKO mice. While E2 replacement reduced steatosis in both Con and LERKO OVX mice, the LERKO OVX mice maintained greater hepatic triglyceride content. E2 replacement promoted greater basal and ADP-stimulated (State 3) mitochondrial respiration in Con OVX but not in LERKO OVX mice under palmitate-supported conditions. Changes in mitochondrial respiration could not be attributed to altered responses to changes in energy demand (GATP) or to alterations in mitochondrial H2O2 production. Conversely, maximal coupled branched-chain amino acid-supported respiration was universally suppressed by E2 replacement. Proteomics analysis revealed E2-mediated reductions in hepatic mitochondrial energy transduction, with relatively minimal differences between Con and LERKO mice. In conclusion, post-ovariectomy estrogen treatment reduces steatosis in the absence of hepatic ER; however, triglyceride levels remain higher, and mitochondrial respiratory deficits persist despite similar proteomic signatures, suggesting that ER signaling is required for optimal estrogen hepatic responsiveness.

biochemistry↗

bioRxiv2025

Hepatic ketogenic insufficiency blunts exercise-induced energy expenditure and alters mitochondrial proteins in skeletal muscle.

Ketone body (KB) utilization increases during fasting and exercise due to enhanced hepatic fatty acid oxidation and KB production via the rate-limiting mitochondrial enzyme hydroxymethylglutaryl-CoA synthase (HMGCS2). Since KB metabolism intersects with multiple metabolic pathways, and skeletal muscle KB catabolism rises during exercise, we tested the hypothesis that liver-specific HMGCS2 knockouts (KO) would have reduced energy expenditure (EE) and changes in the mitochondrial proteome of skeletal muscle with chronic exercise through voluntary wheel running (VWR), time-restricted feeding (TRF), or both combined to boost hepatic KB production and utilization. Control (CON) and HMGCS2 knockout (KO) mice (n=6-8 per group) underwent sedentary ad libitum feeding (SED+AL), SED+TRF, VWR+AL, and VWR+TRF for 16 weeks, with whole-body EE measured using indirect calorimetry. In CON mice, VWR increased total EE by 19.5% and non-resting EE by 50% under AL conditions, and total EE by 16% and non-resting EE by 47.9% under TRF conditions. However, the EE increases seen with VWR did not occur in KO mice. Proteomic analysis revealed that the loss of liver HMGCS2 significantly impacted proteins involved in metabolic processes within skeletal muscle, including reduced oxidative phosphorylation (OXPHOS) protein expression in SED KO mice compared to sedentary CON. Notably, VWR restored OXPHOS protein expression in the muscle of the liver HMGCS2 KO but did not alter it in the CON. Furthermore, muscle from liver HMGCS2 KO mice had elevated expression glycolytic pathways in sedentary and VWR conditions. These results indicate that hepatic ketogenic deficiency (HMGCS2 KO) diminishes exercise-induced increases in EE and uniquely impacts baseline and exercise-related adaptations in the metabolic and mitochondrial proteome of skeletal muscle.

physiology↗

bioRxiv2019

Divergent Energy Expenditure Impacts Mouse Metabolic Adaptation to Acute High-Fat/High-Sucrose Diet Producing Sexually Dimorphic Weight Gain Patterns

ObjectiveLong-term weight gain can result from cumulative small weight increases due to short-term excess caloric intake during weekends and holidays. Increased physical activity may mediate weight gain through increases in energy expenditure (EE) and reductions in energy balance. Current methods for modulating mouse EE (e.g. - exercise, chemical uncouplers, etc.) have confounding effects. However, it is known that mouse EE linearly increases as housing temperature decreases below the thermoneutral zone. MethodsTo determine how robust differences in baseline EE impact 7-day changes in weight and body composition on low-fat and high-fat, high-sucrose (HFHS) diets, we performed indirect calorimetry measurements in male and female mice housed at divergent temperatures (20{degrees}C vs. 30{degrees}C). ResultsAs expected, mice housed at 30{degrees}C have [~]40% lower total EE and energy intake compared to 20{degrees}C mice regardless of diet or sex. Energy balance was increased with HFHS in all groups, with [~]30% greater increases observed in 30{degrees}C versus 20{degrees}C mice. HFHS increased weight gain regardless of temperature or sex. Interestingly, no HFHS-induced weight gain differences were observed between females at different temperatures. In contrast, 30{degrees}C male mice on HFHS gained [~]50% more weight than 20{degrees}C males, and [~]80% more weight compared to 30{degrees}C females. HFHS increased fat mass across all groups but 2-fold higher gains occurred in 30{degrees}C mice compared to 20{degrees}C mice. Females gained [~]35% less fat mass than males at both temperatures. ConclusionsTogether, these data reveal an interaction between divergent ambient temperature-induced EE and sex that impacted diet-induced patterns of short-term weight gain and body composition. HighlightsO_LIUtilized ambient temperature differences as an experimental tool to study the impact of divergent baseline energy expenditure on metabolic adaptation to high-fat, high-sucrose diet. C_LIO_LIBaseline energy expenditure and sex interact to impact diet-induced changes in body composition and weight gain. C_LIO_LIThe energy expenditure and sex interaction is a result of an inverse relationship between fat mass gain and weight-adjusted total energy expenditure, as well as, diet-induced non-shivering thermogenesis. C_LIO_LIThese data support that the hypothesis that higher energy expenditure amplifies the coupling of energy intake to energy expenditure during energy dense feeding, resulting in reduced positive energy balance and reduced gains in weight and adiposity. C_LIO_LIFirst evidence that energy expenditure level plays a role in the composition of weight gained by female mice during acute HFHS feeding. C_LIO_LIThis study further highlights issues with obesity/energy metabolism research performed in mice at sub-thermoneutral housing temperatures, particularly with sex comparisons. C_LI GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/840702v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@39eb69org.highwire.dtl.DTLVardef@8e564forg.highwire.dtl.DTLVardef@c46714org.highwire.dtl.DTLVardef@4b5898_HPS_FORMAT_FIGEXP M_FIG Legend: Male and female mice housed at 30{degrees}C had lower energy expenditure (EE) & energy intake (EI), while having greater energy balance (EB), during 7-day high-fat/high-sucrose (HFHS) feeding compared to male and female mice, respectively, housed at 20{degrees}C. However, female mice had lower EB compared to males at both housing temperature. Female mice housed at 30{degrees}C gained less weight than 30{degrees}C males but gained the same relative amount of fat mass during acute HFHS feeding. Interestingly, 20{degrees}C females gained the same amount of weight as 20{degrees}C males but gained primarily fat-free mass, while the males gained the same proportion of fat as 30{degrees}C males and females. C_FIG

physiology↗