Biology subjects

Jeromson, S.

Publications and source records attributed to Jeromson, S..

6 recordsLinked to original sources

bioRxiv2026

Tirzepatide and Intermittent Cold Exposure Independently Improve Glucose Homeostasis in DIO Mice Housed at Thermoneutrality

Obesity is considered a risk factor for metabolic diseases, including type 2 diabetes, and results from an imbalance between energy intake and energy expenditure. While pharmacological approaches such as tirzepatide, a dual GIP/GLP-1 receptor agonist, effectively reduce food intake and body weight, strategies that enhance energy expenditure (EE) may provide complementary metabolic benefits. Intermittent cold exposure (ICE) is one such approach that enhances EE and improves glucose homeostasis independent of weight loss. However, the combined effects of these interventions remain unexplored. In this study, we investigated the individual and combined effects of tirzepatide and ICE on body composition, energy metabolism, and glucose homeostasis in diet-induced obese (DIO) male and female mice housed at thermoneutrality. After 8 weeks of 45% high-fat diet feeding, mice received tirzepatide (10 nmol/kg) or vehicle and were exposed to ICE (4{degrees}C, 1 h/day, 5 days/week) or remained at thermoneutrality for 3 weeks. Energy expenditure and substrate utilization were assessed using indirect calorimetry at thermoneutrality and during an acute 1 h cold challenge. Tirzepatide reduced body weight, food intake, and adiposity in both sexes, with a greater reduction in lean mass in males. ICE did not affect body weight but improved glucose homeostasis. At thermoneutrality, tirzepatide did not alter total EE but lowered respiratory exchange ratio (RER), indicating a shift toward lipid utilization. In contrast, ICE increased energy expenditure and fat oxidation, with no additive effects observed when combined with tirzepatide. Together, these findings highlight that targeting both energy intake and expenditure represents complementary, but not necessarily additive approaches to improving metabolic health.

physiology↗

bioRxiv2025

Glucagon-induced PGC-1α4/PPARγ promotes hepatic lipid storage and macrosteatosis in fasting and MASLD

The liver plays a central role in regulating the transition between fasting and feeding states, coordinating glycogen breakdown, gluconeogenesis, fatty acid catabolism, and lipid storage. Disruptions in this balance contribute to metabolic disorders, including Metabolic dysfunction Associated Steatotic Liver Disease (MASLD). Here, we identify a novel biological pathway downstream of glucagon that promotes the hepatic lipid accumulation associated with fasting. Using gain- and loss-of-function in vivo and in vitro models, we found that glucagon induces sustained expression of PGC-14, promoting lipid uptake and storage in hepatocytes by increasing PPAR{gamma} activity. Increased PPAR{gamma}/PGC-14 promotes hepatic Fsp27/Cidec expression, leading to lipid droplet expansion and triglyceride trapping in liver. Activity of the PPARGC1A alternative promoter and PGC-14 expression were higher in livers of patients with MASLD, and PGC-14 expression correlated with macrosteatosis. Consistently, persistent expression of hepatic PGC-14 in mice fed a western diet promoted macrosteatosis, exacerbated oxidative stress and altered hepatic lipid composition to resemble worsening Metabolic dysfunction Associated Steatohepatitis (MASH) in humans. Our findings demonstrate that glucagon-induced hepatic PGC-14/PPAR{gamma} activity facilitates efficient uptake and storage of lipids during fasting, but over-activation of this coordinated metabolic pathway leads to lipid accumulation and worsening of steatosis in MASLD.

physiology↗

bioRxiv2025

Protective effects of central leptin on whole-body energy homeostasis upon acute olanzapine exposure

Second-generation antipsychotic use is associated with severe metabolic side effects such as obesity and type 2 diabetes. Leptin is a hormone that is secreted by adipose tissue, and it acts on the brain to decrease body weight by reducing food intake and stimulating energy expenditure. Leptin also improves glucose and lipid metabolism. We examined the short-term impact of olanzapine, a commonly used second-generation antipsychotic, on the central leptin-mediated regulation of energy balance, lipid metabolism, and hypothalamic kinase activity. Male Sprague Dawley rats were given an acute intracerebroventricular (ICV, 3rd ventricle) injection of either leptin or vehicle, combined with subcutaneous olanzapine or vehicle. As expected, ICV leptin decreased food intake and importantly, olanzapine did not block this effect. Administration of leptin, olanzapine, or their combination reduced the average respiratory exchange ratio (RER) during the light cycle, which indicates that fat oxidation was increased. In the dark cycle, leptin decreased the average RER regardless of olanzapine administration, and in the presence of leptin, olanzapine did not affect the average RER. Leptin did not alter the olanzapine-induced increase in serum triglyceride concentrations. Olanzapine and central leptin treatment differentially activated hypothalamic kinases. In conclusion, regulation of food intake and fuel preference by central leptin is intact following acute olanzapine administration.

neuroscience↗

bioRxiv2025

Topical application of the cold-mimetic L-menthol decreases wheel running without affecting the beneficial effects of voluntary exercise in mice

Topical application of L-menthol, a pharmacological cold-mimetic and agonist of the cold-sensing receptor TRPM8 (Transient Receptor Potential Cation Channel Subfamily M Member 8), has been shown to stimulate brown adipose tissue (BAT) thermogenesis and reduce weight gain in both obese and lean male mice, without affecting energy intake. While these findings suggest that L-menthol could offer a novel approach to prevent weight gain, its potential to enhance the benefits of exercise on whole-body metabolic health remains unexplored. In this study, we investigated whether daily topical L-menthol application, combined with voluntary wheel running, could enhance exercise-induced improvements in metabolic health in male and female C57BL/6J mice housed at thermoneutrality (29{degrees}C). Our results demonstrated that although L-menthol treatment reduced voluntary wheel running distance there was still a main effect of exercise to reduce fat mass, weight gain and improve glucose tolerance. Indirect calorimetry revealed that L-menthol increased total energy expenditure, potentially explaining improvements in metabolic health despite reductions in voluntary wheel running. These findings suggest that although L-menthol does not enhance the effects of voluntary exercise, it remains a promising strategy for improving metabolic health. Key pointsO_LIL-menthol treatments led to a reduction in voluntary wheel running distance C_LIO_LIDespite the reduced voluntary exercise with L-menthol, wheel running led to significant reductions in fat mass as well as improved glucose tolerance C_LIO_LITreatment with L-menthol increased energy expenditure perhaps providing an explanation for exercise-induced improvements in indices of metabolic health despite reduction in wheel running C_LI

physiology↗

bioRxiv2020

Protein-carbohydrate ingestion alters Vps34 cellular localization independent of changes in kinase activity in human skeletal muscle

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell size and growth in response to nutrients, however, the mechanisms by which nutrient levels are sensed by mTORC1 in human skeletal muscle are yet to be fully elucidated. The Class III PI3Kinase Vps34 has recently been proposed as a sensor essential for mTORC1 activation following nutrient stimulation. We therefore investigated the effects of increasing nutrient availability through protein-carbohydrate (PRO-CHO) feeding on Vps34 kinase activity and cellular localization in human skeletal muscle. Eight young, healthy males (age - 21 {+/-} 0.5yrs, mean {+/-} SEM) ingested a PRO-CHO beverage containing 20/44/1g PRO/CHO/FAT respectively, with skeletal muscle biopsies obtained at baseline and 1h and 3h post-feeding. PRO-CHO feeding did not alter Vps34 kinase activity, but did stimulate Vps34 translocation toward the cell periphery (PRE (mean{+/-}SEM) - 0.273{+/-}0.021, 1h - 0.347{+/-}0.022, Pearsons Coefficient (r)) where it co-localized with mTOR (PRE - 0.312{+/-}0.018, 1h - 0.348{+/-}0.024, Pearsons Coefficient (r))). These alterations occurred in parallel to an increase in S6K1 kinase activity - 941{+/-}164% of PRE at 1h post-feeding). Subsequent in vitro experiments in C2C12 and human primary myotubes displayed no effect of the Vps34-specific inhibitor SAR405 on mTORC1 signalling responses to elevated nutrient availability. Therefore, in summary, PRO-CHO ingestion does not increase Vps34 activity in human skeletal muscle, whilst pharmacological inhibition of Vps34 does not prevent nutrient stimulation of mTORC1 in vitro. However, PRO-CHO ingestion promotes Vps34 translocation to the cell periphery, enabling Vps34 to associate with mTOR. Therefore, our data suggests that interaction between Vps34 and mTOR, rather than changes in Vps34 activity per se may be involved in PRO-CHO activation of mTORC1 in human skeletal muscle.

physiology↗

bioRxiv2019

PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments

Liver is regularly exposed to changing metabolic and inflammatory environments. It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. PGC-1 is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation. However, it is not known how PGC-1 integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1 exists as multiple, alternatively spliced variants expressed from different promoters. Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1 proteins in regulating hepatic metabolism and inflammatory signaling downstream of TNF. PGC-11 and PGC-14 were expressed in hepatocytes and expression analysis uncovered shared and isoform-specific roles for these variants linked to metabolism and inflammation. PGC-11 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNF signaling revealed that PGC-14 influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models illustrated that PGC-14 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNF or LPS. This was in contrast to PGC-11, which reduced the expression of a wide inflammatory gene network, but did not prevent liver cell death in response to the cytokine. We conclude that PGC-1 variants have distinct, yet complimentary roles in hepatic responses to metabolism and inflammation and identify PGC-14 as an important mitigator of apoptosis.

molecular biology↗