Biology subjects

Gunes, A.

Publications and source records attributed to Gunes, A..

3 recordsLinked to original sources

bioRxiv2026

The PGC-1α Gly482Ser rs8192678 SNP reprograms oxidative metabolism to favor energy storage in females

The Gly482Ser SNP (rs8192678) in the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene has been associated with obesity, type 2 diabetes and other human metabolic diseases. In this study, we found that human iPSCs carrying a serine risk allele had reduced respiratory capacity, and individuals living with overweight or obesity homozygous for the serine allele (S/S) exhibited a preference for carbohydrate oxidation following a high-fat meal. Using a PGC-1Ser481Gly knock-in mouse model, we performed metabolic phenotyping of male and female mice carrying the three genotypes (G/G, S/G, S/S) under acute nutritional challenges (chow, fasting and high-fat high-sugar (HFHS) feeding) and chronic HFHS feeding. S/S females were heavier and showed a trend toward an increased respiratory exchange ratio (RER) during fasting, with greater weight gain and fat mass following chronic HFHS feeding. Transcriptomic analyses revealed tissue-specific reprogramming of mitochondrial oxidative pathways, that were downregulated in subcutaneous adipose tissue and liver while upregulated in muscle, with the strongest effects observed in S/S females. Together, these findings provide in vivo evidence that this SNP reprograms whole-body oxidative metabolism, with a net effect of favoring carbohydrate oxidation and energy conservation, particularly in females.

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↗

bioRxiv2020

Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease

ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is a growing epidemic associated with key aspects of metabolic disease such as obesity and diabetes. The first stage of NAFLD is characterized by lipid accumulation in hepatocytes, but this can further progress into non-alcoholic steatohepatitis (NASH), fibrosis or cirrhosis, and hepatocellular carcinoma (HCC). A western diet, high in fats, sugars and cholesterol is linked to NAFLD development. Murine models are often used to experimentally study NAFLD, as they can display similar histopathological features as humans; however, there remains debate on which diet-induced model most appropriately and consistently mimics both human disease progression and pathogenesis. In this study, we performed a side-byside comparison of two popular diet models of murine NAFLD/NASH and associated HCC: a high fat diet supplemented with 30% fructose water (HFHF) and a western diet high in cholesterol (WDHC), comparing them to a common grain-based chow diet (GBD). Mice on both experimental diets developed liver steatosis, while WDHC-fed mice had greater levels of hepatic inflammation and fibrosis than HFHF-fed mice. In contrast, HFHF-fed mice were more obese and developed more severe metabolic syndrome, with less pronounced liver disease. Despite these differences, WDHC-fed and HFHF-fed mice had similar tumour burdens in a model of diet-potentiated liver cancer. Response to diet and resulting phenotypes were generally similar between sexes, albeit delayed in females. Notably, although metabolic and liver disease phenotypes are often thought to progress in parallel, this study shows that modest differences in diet can significantly uncouple glucose homeostasis and liver damage. In conclusion, long-term feeding of either HFHF or WDHC are reliable methods to induce NASH and diet-potentiated liver cancer in mice of both sexes; however, the choice of diet involves a trade-off between severity of metabolic syndrome and liver damage.Competing Interest StatementThe western diet high in cholesterol (WDHC) was provided by ResearchDiets. Data was discussed with staff at ResearchDiets prior to publication; however, they were not involved in experimental design, data analysis, data interpretation or writing of the manuscript.View Full Text

physiology↗