Dysregulation of glucose and lipid metabolism is closely linked to metabolic diseases such as obesity, diabetes, and diabetic nephropathy, posing serious threats to human health. Orosomucoid (ORM), an acute-phase protein, exhibits diverse biological functions such as immunomodulation, drug transport, and barrier maintenance. Accumulating evidence has recently revealed ORM's critical regulatory role in metabolic processes. Studies indicate that ORM modulates glucose and lipid metabolism through multiple mechanisms, including regulating food intake, attenuating adipose tissue inflammation and fibrosis, inhibiting adipocyte differentiation and hepatic steatosis, and promoting glycogen synthesis. This review systematically examines the regulatory mechanisms of ORM expression under inflammatory and metabolic stress conditions, the effects of ORM on glucose and lipid homeostasis, and its clinical associations with metabolic diseases. These insights could inform innovative strategies for preventing and treating metabolic diseases.

Because higher adiposity is associated with cardiometabolic disease, we assessed the relationship between body composition (body fat percentage; BF%) and postprandial metabolic flexibility [change in respiratory exchange ratio (RER) from fasting]. Young adults [ = 27, = 15 females, body mass index (BMI) = 27.1 ± 4.5; BF% = 30.4 ± 8.7; mean ± SD] without overt pathology completed a 100 g oral glucose tolerance test (OGTT). Indirect calorimetry before (fasting) and following (30, 60, 90, and 120 min) consumption was used to calculate respiratory exchange ratio (RER) and oxidation of carbohydrates (CHOX) and fats (FOX). Serum and plasma were collected at corresponding time points and analyzed for glucose, insulin, and nonesterified fatty acids (NEFAs). Two-way repeated measures ANOVA was used to compare data between normal weight and overweight/obesity by BMI. The effect of BF% on postprandial metabolic flexibility was tested via linear mixed models while adjusting for potential confounders. During the OGTT, blood glucose, serum insulin, plasma lactate, RER, and CHOX all significantly increased, whereas plasma NEFAs and whole body FOX decreased (all < 0.05). BF% modified the relationship between postprandial RER and time ( = 0.019); individuals with higher BF% increase their RER faster and to a greater extent (i.e., greater metabolic flexibility) than those with lower BF%. Body fat percentage is associated with greater postprandial metabolic flexibility during an OGTT in young adults. Despite increased adiposity, metabolic flexibility may be preserved, representing a compensatory adaptation to decreased glucose storage in the postprandial period. Previous studies have suggested that obesity blunts postprandial metabolic flexibility. By directly analyzing the effect of body composition on postprandial metabolic flexibility, we show that healthy young adults with higher body fat percentages have increased postprandial metabolic flexibility in response to concurrent hyperglycemia. This suggests a preserved, metabolically flexible phenotype in young adults with higher body fat percentages.

UCP1, a mitochondrial protein traditionally regarded as exclusive to thermogenic adipocytes, and -promoter-driven Cre is widely used in gene manipulation in thermogenic adipocytes. However, new evidence suggests that -promoter-driven Cre is also active in non-adipocyte types. The presence and role of UCP1 in non-adipose tissues during development, and its potential non-thermogenic functions, remain under debate. This study systematically investigated UCP1 expression patterns from embryogenesis to adulthood using (knock-in), (knock-in) and (transgenic) mice crossed with Ai9-tdTomato-Red mice, complemented by single-cell RNA sequencing and immunostaining analyses. knockout mice were utilized to evaluate developmental consequences of UCP1 deficiency. Significantly, UCP1 expression initiated in non-thermogenic tissues by embryonic day 10.5, before adipose tissue formation, notably in the brain, eye, ear, mammary gland, kidney, and reproductive systems. UCP1 was more broadly expressed in non-adipose tissues during embryonic stages compared to adulthood, particularly in the epithelial cells of these non-adipose tissues. UCP1 knockout mice exhibited retinal developmental defects, suggesting physiological roles for UCP1 beyond thermogenesis in non-adipose tissues. This study highlights that using -promoter-driven tamoxifen-inducible Cre can minimize off-target effects in gene manipulation of thermogenic adipocytes compared to the traditional transgenic Cre strategy.

We previously identified Jumonji domain-containing 8 (JMJD8) as a regulator of lipid droplet (LD) hypertrophy in adipocytes through modulation of AMPK-dependent perilipin-2 (PLIN2) phosphorylation. Given PLIN2's established role in hepatic steatosis, we investigated whether JMJD8 also regulates lipid accumulation in the liver. Here, we report that JMJD8 expression is significantly elevated in the livers of mice fed either a high-fat diet (HFD) or the metabolic-associated fatty liver disease (MAFLD)-inducing Gubra Amylin NASH (GAN) diet. To define the metabolic role of JMJD8 in the liver, we generated liver-specific knockout () mice. Hepatic deletion of reduced triglyceride (TG) accumulation under both dietary conditions, without affecting overall body weight or adiposity. Lipidomic analyses revealed a redistribution of lipid classes in knockout livers on HFD, with decreased storage lipids and increased membrane phospholipids. mice also displayed improved insulin sensitivity and glucose tolerance under HFD but not the GAN diet. Mechanistically, although JMJD8 interacts with PLIN2, its prosteatotic effect appears to be independent of PLIN2. These findings indicate that JMJD8 promotes hepatic steatosis and metabolic dysregulation under HFD by altering lipid class distribution, highlighting its potential as a therapeutic target in obesity-associated metabolic disease. This study identifies Jumonji domain-containing 8 (JMJD8) as a previously unrecognized driver of hepatic steatosis and metabolic dysfunction in diet-induced fatty liver disease. Liver-specific deletion of protects against triglyceride accumulation and insulin resistance, redirecting hepatic lipid composition from energy storage toward membrane remodeling. These findings establish JMJD8 as a key intracellular regulator of lipid homeostasis and glucose metabolism and highlight its potential as a therapeutic target for metabolic-associated fatty liver disease.

The brain has been suggested to regulate glucose metabolism in response to insulin in various tissues. As many of these findings have not been studied in humans, we aimed to assess the effects of intranasal insulin (INI) on brain and peripheral tissue-specific glucose uptake in lean, healthy men. On two separate visits, ten volunteers received either 160 IU INI or placebo during a low-dose hyperinsulinemic, euglycemic clamp in a randomized, single-blinded, crossover design. Tissue glucose uptake was quantified using positron emission tomography (PET) and glucose analogue radiotracer 2-deoxy-2[F]fluoro-D-glucose ([F]FDG), with a dynamic scan starting from 40 minutes after INI. Tissue volumes and radiodensities were assessed with computed tomography. INI induced a global decrease in brain glucose uptake in all participants, with the magnitude of the effect correlating with the amount of visceral adipose tissue. In contrast, INI had no significant effect on skeletal muscle, liver or adipose tissue glucose uptake. To conclude, a single dose of INI does not have a direct effect on peripheral glucose metabolism in healthy, lean men, but the previously reported hypothalamic response is accompanied by a global decrease in cerebral glucose metabolism.

Maternal exercise is a widely recommended and safe intervention associated with the improvement of maternal gestational and infant metabolic health. Although various modes of exercise are deemed safe during pregnancy, the effects of supervised maternal aerobic, resistance, and combination (aerobic + resistance) exercise remain understudied. Specifically, it remains unknown how different modes of maternal exercise affect the placenta, an organ central to maternal-fetal communication and successful pregnancy outcomes. This study aimed to characterize the placental proteomic changes in response to controlled and supervised maternal exercise during gestation. Results demonstrate that the placental proteomic landscape changes in a maternal exercise mode-specific way. In addition, proteomics revealed that ∼20% of the identified placental proteins were associated with maternal exercise volume during gestation. These results highlight the differential effect maternal exercise modes have on the placental proteome and further implicate the placenta in mediating the effects of maternal exercise on maternal and infant health. ClinicalTrials.gov Identifier: NCT03838146 and NCT04805502. This article highlights the broad and significant changes that occur in the placental proteome in response to different types of maternal exercise. Our findings further reveal that the overall volume of maternal exercise was associated with alterations in nearly 25% of the identified placental proteins, suggesting that both the type and amount of maternal physical activity may play important roles in shaping placental function and possibly contributing to fetal development.

Regulated secretion of insulin from β-cells, glucagon from α-cells, and somatostatin from δ-cells is necessary for the maintenance of glucose homeostasis. The release of these hormones from pancreatic islets requires the assembly and disassembly of the SNARE protein complex to control vesicle fusion. Complexin 2 (Cplx 2) is a small soluble synaptic protein that participates in the priming and release of vesicles. It plays a dual role as a molecular switch that clamps and prevents fusion pore opening, which subsequently undergoes a conformational change upon Ca binding to synaptotagmin to facilitate exocytosis. Using a Cplx 2 knockout (KO) mouse model, we show a direct inhibitory role of Cplx 2 for glucagon and somatostatin secretion, along with an indirect role in the paracrine inhibition of insulin secretion by somatostatin. Deletion of Cplx 2 increases glucagon and somatostatin secretion from intact mouse islets, whereas there is no effect on insulin secretion. The normal paracrine inhibition of insulin secretion by somatostatin is disrupted in Cplx 2 KO islets. On the contrary, deletion of Cplx 2 did not affect the paracrine inhibition of glucagon by somatostatin at elevated glucose levels. In both β- and α-cells, the secretion profiles are parallel to Ca activity changes following somatostatin treatment of wild-type (WT) and Cplx 2 KO islets. The loss of paracrine inhibition of insulin secretion is substantiated by direct measurements of insulin vesicle fusion events in Cplx 2 KO islets. Together, these data show a differential role for Cplx 2 in regulating hormone secretion from pancreatic islets. Complexin 2 (Cplx 2) is a small synaptic protein that functions to clamp and release the SNARE protein complex during exocytosis. We show that Cplx 2 has a direct inhibitory role in glucagon and somatostatin secretion from intact mouse islets. Furthermore, the deletion of Cplx 2 leads to disrupted inhibition of β-cell Ca activity and insulin secretion by somatostatin. These findings highlight a differential regulatory role of Cplx 2 in hormone secretion from pancreatic islets.

Although it is well established that animals adapted to a high-protein, carbohydrate-free (HP) diet maintain glycemia through enhanced hepatic gluconeogenesis, the regulatory factors and molecular mechanisms underlying this adaptation remain incompletely understood. Given the chronically elevated glucagon levels observed in these animals, we hypothesized that the cAMP/PKA/CREB signaling pathway might contribute to the enhanced gluconeogenic capacity observed in HP-fed mice. Although CREB activity was transiently increased during early HP feeding, it became attenuated upon prolonged exposure. This attenuation correlated with elevated hepatic GRK2 content, likely driven by increased circulating branched-chain amino acids (BCAAs) and suppression of hepatic autophagy. Exploring alternative regulatory pathways, we identified impaired insulin signaling and reduced phosphorylation and acetylation of hepatic FoxO1 in HP-adapted mice, supporting a central role for FoxO1 in sustaining gluconeogenesis. Consistently, pharmacological inhibition of FoxO1 reduced hepatic gluconeogenesis and glycemia, and suppressed the liver expression of , , and , key transcriptional coactivators associated with long-term gluconeogenic regulation. Furthermore, we found that elevated corticosterone levels in HP-adapted animals were essential for maintaining hepatic gluconeogenesis and its fasting glycemia. Together, our findings reveal a shift in the regulatory landscape of hepatic gluconeogenesis during HP feeding, transitioning from early CREB activation to a sustained FoxO1-driven transcriptional program. The regulation of hepatic glucose production under a high-protein (HP) diet remains unclear. We show that gluconeogenesis in HP-fed mice is initially driven by CREB but shifts to FoxO1 dependence over time. Notably, FoxO1 is essential for maintaining gluconeogenesis and glycemia in HP-adapted animals. We also reveal a key role for corticosterone in preserving gluconeogenic capacity and fasting glycemia. These findings provide insights into hepatic metabolic adaptation and into molecular mechanisms governing glycemic homeostasis.

Regular aerobic exercise decreases the risk of metabolic diseases; however, reduced physical activity may attenuate these beneficial adaptations. This study investigated the influence of a single day of reduced activity on the skeletal muscle transcriptome (RNASeq) and systemic metabolism surrounding an acute bout of aerobic exercise. Utilizing a crossover design, subjects (n=9 [7M, 2F], 24±1y) exercised at 65% VOmax for 60-minutes following a day of reduced activity (IN; 3,581±1,185 steps) and normal activity (A; 11,069±3,631 steps). RNAseq from skeletal muscle biopsies were taken before and 4-hours post-exercise. Respiratory gas exchange analysis was completed at 20, 40, and 60 minutes of exercise. Blood samples for select metabolites were collected before, during, and throughout the 4-hour recovery. Inactivity resulted in nine Differentially Expressed Genes (DEG) at rest, while exercise altered 793 and 1,403 genes in A and IN, respectively. Gene set enrichment analysis revealed an interaction of exercise and trial, which were related to inflammation, metabolism, cell cycle, and innate immunity. Respiratory exchange ratio (0.93±0.04 vs. 0.91±0.03; p<0.05) and carbohydrate utilization (2.16±0.79 vs. 1.96±0.72 g/min; p=0.09) were higher in the IN vs. A trial at 60-minutes of exercise. Triglycerides were higher in the IN trial (p<0.05), with no differences between trials observed in other measured metabolites. These findings indicate that a single day of reduced physical activity can elicit modest but significant changes in the metabolic and transcriptomic exercise response. Such alterations have implications for exercise guidelines and underscore the importance of controlling for daily step count when assessing exercise responses.

The accurate estimation of daily energy requirements is important to inform athletes about their caloric needs and to prevent long-term low energy availability. Such estimations are often done by estimating energy expenditure. Recent data, including from a 200+ athlete cohort, show systematic under-prediction of resting metabolic rate (RMR); we tested this specifically in elite male volleyball players, who represent an under-represented sport and a body morphology that is lacking in the literature. The purpose of this investigation is to compare the estimates of currently recommended predictive RMR equations for athletes (Harris-Benedict, Cunningham, Freire, Ten Haaf and Tinsley) against measured RMR using high-resolution indirect calorimetry in volleyball players. Using a cross-sectional design, 22 international (tier 4) elite male volleyball players underwent evaluations of body composition, RMR, bloodwork and completed the three-factor eating questionnaire-R18. Participants had a body mass of 93.3 ± 8.7 kg, fat-free mass of 77.5 ± 7.7 kg and %body fat of 17.0 ± 2.2 %. Our main findings were 1) the Ten Haaf (-134.9 ±151 kcal (95%CI)), Freire (-181.4 ±156 kcal (95%CI)), Harris-Benedict (-256.4 ±152 kcal (95%CI)), and Cunningham (-299.8 ±150 kcal (95%CI)) equations under predicted RMR compared to indirect calorimetry (p<0.05), 2) the Tinsley equation was the most accurate (-126.8 ±150 kcal (95%CI)), but moderately reliable (ICC=0.59), at estimating RMR compared to indirect calorimetry and 3) due to proportional bias towards heavier players, the RMR ratio <0.90 with the Tinsley equation was not reliable to detect individual volleyball players at greater of energy deficit. Future work should explore novel metabolic assessment protocols that will reliably assess energy needs of athletes high in absolute FFM.

Recurrent pregnancy loss (RPL) is a multifactorial condition, with nearly half of cases remaining unexplained, and maternal insulin resistance is identified as a significant contributor. This study examined the role of SIK1 in RPL patients associated with insulin resistance using villi samples, in vitro trophoblast models, and an insulin resistant mouse model. Our results revealed that a marked increase in miscarriage risk was observed in women with higher value of homeostatic model assessment for insulin resistance (>2.41). SIK1 expression was elevated in the villous tissues of RPL patients with insulin resistance, as well as insulin-treated trophoblast models. Overexpression of SIK1 impaired trophoblast migration and invasion by downregulating MMP2 and MMP9, and disrupted decidual natural killer cell-mediated vascular remodeling. Co-cultured decidual natural killer cells exhibited altered cytokine expression, leading to endothelial dysfunction. In vivo, insulin resistant mice showed elevated placental SIK1 expression, reduced pregnancy success, and defective spiral artery remodeling. These findings suggest that SIK1 activation driven by insulin resistance impairs trophoblast and decidual natural killer cell functions, thereby contributing to recurrent pregnancy loss.

Insulin released in response to a stepwise increase in glucose (square wave) is biphasic with a transient 5-10 min first-phase peak and a more sustained second phase. While the first phase is generally assumed to be rate-dependent and the second concentration-dependent, detailed studies of first-phase rate-sensitivity are lacking. We performed dynamic perifusion studies with human islets using customizable glucose ramps and established the corresponding insulin secretion time-profiles. First-phase release was defined as the excess insulin above that expected from the concentration-dependent second phase, and its dependence on the glucose gradient (rate of increase) was examined. The first-phase insulin release rate calculated this way increased with the gradient and fit well to a Hill-type sigmoid function with a half-maximal value around 1.25 mM/min (=1.8, =0.96). This aligns with our previously introduced glucose-insulin control system built on a general framework of a sigmoid proportional-integral-derivative (σPID) controller, a generalized PID controller more suitable for biological systems than linear ones as responses are bounded between zero and a maximum. Experimental results were used to slightly recalibrate this local glucose concentration-based computational model resulting in predictions in good agreement with measured first- and second-phase insulin secretions (>0.90). Thus, glucose-stimulated insulin secretion (GSIS) of perifused human islets can be described well as the sum of a mainly rate-sensitive first phase, which is a sigmoid function of the glucose gradient with half-maximal activation around 1.25 mM/min, and a concentration-sensitive second phase, which is a sigmoid function of the glucose concentration with half-maximal activation near 8 mM.

Steatotic liver disease (SLD) is a spectrum of chronic and progressive disorders. While often associated with obesity, it can afflict individuals without obesity, including infants. We previously reported that neonatal pigs fed formulas enriched with medium- (MCFA), rather than long-chain (LCFA) fatty acids, developed steatosis by day 7 and steatohepatitis by day 14. Here, we examined hepatic regulation of lipolytic and lipogenic pathways and associated metabolic outcomes. Neonatal pigs (=18) were fed isocaloric formulas containing MCFA or LCFA for 7, 14 or 21 days. Transcript abundance of most lipolytic and lipogenic genes was greater in MCFA- than LCFA-fed pigs, independent of feeding duration. Upregulation of lipolytic genes of MCFA fed pigs corresponded with greater lauric ( = 0.04) and palmitic ( = 0.03) acid oxidation, and greater plasma β-hydroxybutyrate concentrations than LCFA counterparts ( = 0.06). Upregulation of lipogenic genes in the MCFA group coincided with greater hepatic medium- (C12:0, C14:0) and long- (C16:0, C16:1) chain fatty acid concentrations ( < 0.05), and greater de novo lipogenic index at all time points ( < 0.001) compared with LCFA group. Principal component and partial least squares analyses indicated that MCFA-fed pigs clustered with upregulated lipogenic, lipolytic, and transport genes, and associated with greater medium-chain fatty acids, and hepatic fat. However, LCFA-fed pigs clustered with greater polyunsaturated fatty acids and reduced transcript abundance of these genes. These findings demonstrate that pediatric SLD pathophysiology involves metabolic adaptations where fatty acid uptake and synthesis overwhelms the liver's oxidative or export capacity, causing net lipid accumulation.

Cocaine- and amphetamine-regulated transcript peptide inhibits food and water intake in rodents and there is evidence that the peptide interacts with the previously orphaned G protein-coupled receptor GPR160. In addition, the peptide transmits pain signals in spinal cord and loss of expression blocks spinal nerve injury pain perception. Using the same animal model as that employed to demonstrate the necessity of expression for pain perception, we examined food and water intakes under conditions and following acute stress. We report that total daily food and water intakes in knockout animals do not significantly differ from those in expressing controls, but meal patterning is altered. On the other hand, food intake following an acute stress is altered. We conclude that in mice activation of GPR160 is not essential for unstimulated food and water ingestion, but that loss of receptor expression is sufficient to change the patterning of ingestive behavior.

Aerobic fitness is associated with greater skeletal muscle insulin sensitivity with regards to glucose uptake. Whether fitness is associated with an improvement in the insulin36 regulation of adipose tissue lipolysis is unknown.

Hashimoto's thyroiditis (HT) is a prevalent autoimmune disease marked by lymphocytic infiltration and progressive destruction of the thyroid gland. The pathogenesis involves cytotoxic T lymphocytes, while regulatory T cells (Tregs), identified by the transcription factor FOXP3, are crucial for maintaining self-tolerance. This study aimed to investigate the composition of HT' lymphocyte infiltrate and the expression of FOXP3 and PD-L1 within HT patients' thyroid tissue aiming to clarify their roles in this chronically activated immune environment. This cross-sectional study analyzed surgical thyroid specimens from 18 patients with HT and 12 non-autoimmune controls. Immunohistochemistry was used to evaluate the expression of CD4+, CD8+, CD20+, FOXP3, and PD-L1 markers in the tissue. HT group had significantly higher expression of CD4+, CD8+, and CD20+ lymphocytes. While CD25+ expression was similar between groups, FOXP3 was positive in 100% of HT samples versus only 8.3% of controls. HT was associated with PD-L1 follicular cell expression in both the cytoplasm and cell membrane, a pattern distinct from the predominantly cytoplasmic expression in controls. In conclusion, this study demonstrates that HT involves a dense intrathyroidal infiltrate of effector T cells, B cells, and FOXP3+ Treg cells. The higher prevalence of FOXP3 without a corresponding higher prevalence of CD25+ suggests a population of chronically activated Tregs within the inflamed gland. The distinct expression pattern of PD-L1 in follicular cells indicates that the PD-1/PD-L1 pathway is actively engaged, possibly as a protective feedback mechanism against autoimmune destruction. These findings help clarify the local immunoregulatory network in HT and highlight Tregs and the PD-1/PD-L1 axis as promising targets for future therapeutic interventions.

A carbohydrate-rich breakfast is commonly consumed by cyclists to compensate for an overnight decline in liver glycogen content and, as such, to maximize liver glycogen stores in the hours before exercise. However, the extent to which liver glycogen content increases in response to the intake of a carbohydrate-rich breakfast in well-trained cyclists remains unexplored. Twelve well-trained male cyclists (age: 25 ± 5 yr; V̇o: 67 ± 5 mL·min·kg; W: 5.8 ± 0.7 W·kg) participated in this trial. Carbon-13 magnetic resonance spectroscopy (C-MRS) at 7 T and magnetic resonance imaging (MRI) at 3 T were applied to assess muscle and liver glycogen concentrations and volume, respectively, before and 3 h after ingesting a carbohydrate-rich breakfast providing 3 g carbohydrates per kg body mass. Following breakfast ingestion, muscle glycogen concentrations, muscle volumes, and total muscle glycogen content did not change ( > 0.05). Liver glycogen concentrations increased by ∼10% (from 164 ± 30 to 180 ± 33 mmol/L; = 0.036), whereas liver volumes decreased by ∼6% (from 1.96 ± 0.28 to 1.84 ± 0.27 L; < 0.001) in the 3 h following breakfast ingestion. Consequently, no net change in overall liver glycogen content was observed following breakfast ingestion (from 53 ± 15 to 54 ± 13 g; = 0.516). Ingesting a carbohydrate-rich breakfast (providing 3 g carbohydrates per kg body mass) does not elevate liver or muscle glycogen content during the subsequent 3-h postprandial period. This is the first study to simultaneously assess both muscle and liver glycogen content following ingestion of a practical carbohydrate-rich breakfast in well-trained cyclists. No changes were observed in muscle glycogen concentrations or content. Liver glycogen concentrations increased postprandially, but liver glycogen content remained unchanged due to a concurrent decline in liver volume. These findings highlight the importance of accounting for liver volume changes when interpreting postprandial liver glycogen storage responses.

Mitogen-activated protein kinases play an essential role in the onset of hepatic metabolic dysregulation; however, current data fail to establish a definitive role for p38. We generated a hepatocyte-specific p38α knockout (p38α KO) mouse model to investigate the role of p38α in regulating hepatic glucose and lipid metabolism following 1 week of high-fat diet (HFD) feeding. Short-term HFD-feeding increased hepatic p38 activation in mice. Hepatocyte-specific p38α KO mice were protected from the development of HFD-induced hepatic insulin resistance, in part due the abolition of circulating interleukin-6 (IL-6). Unexpectedly, hepatocyte-specific p38α KO mice were also protected from HFD-induced peripheral insulin resistance. The liver-peripheral tissue axis underlying the onset of HFD-mediated peripheral insulin resistance may be explained by muscle fat accumulation promoted by p38α-mediated hepatic triglyceride (TG) secretion. HFD-induced activation of p38α promoted TG accumulation in the liver, potentially via enhanced expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and subsequent regulation of perilipin gene expression. Overall, our data provide compelling evidence that selective p38α inhibition may offer a new approach for the treatment of insulin resistance and hepatic steatosis.

The Western diet, rich in fats and sugars such as fructose, contributes significantly to the global rise in obesity and type 2 diabetes. While both high-fat and high-fructose diets ( and ) are known to impair hepatic insulin signaling, the specific mechanisms and potential sex-specific differences remain underexplored. Moreover, the role of hepatic androgen receptor () in modulating these effects, particularly in females, has not been fully elucidated. Here, we investigated the contribution of hepatic AR to HFrD-induced metabolic dysfunction using liver-specific AR knockout () mice of both sexes. Male and female LivARKO and wild-type () littermates were subjected to either a HFrD or calorie-matched control diet from 4 to 12 weeks of age and underwent several metabolic tests during months one and two. Glucose tolerance tests () conducted during month one revealed that WT-HFrD females developed significant glucose intolerance, while LivARKO-HFrD females exhibited partial protection, demonstrating improved glucose clearance relative to their WT counterparts. These effects appeared sex-specific, as male LivARKO mice did not exhibit similar protective effects under HFrD conditions. Our findings suggest that hepatic AR plays a sex-specific role in mediating fructose-induced insulin resistance, and its deletion in females confers partial protection against diet-induced metabolic impairments by improving hepatic insulin signaling and regulating gluconeogenic genes. This highlights the importance of considering sex and hepatic androgen signaling in the development of targeted therapies for diet-induced metabolic disorders.