Dataset Information

Understanding how reduced energy intake rapidly alleviates obesity associated insulin resistance

ABSTRACT: Insulin resistance (IR) underpins the relationship between obesity and its associated metabolic disorders. Negative energy balance alleviates IR rapidly, though the mechanism remains unclear. Here, we show that in obese mice, IR can be reversed by calorie reduction (CR) within a day. In the liver, improved insulin sensitivity correlates with reduced tri-(TAG) and diacylglycerol (DAG) concentrations and decreased protein kinase C epsilon (PKCε) activation. In muscle, insulin-stimulated glucose disposal was also restored, whereas obesity-related changes in adipose tissue largely persisted following CR. Specifically, obesity is associated with reduced fasting lipolytic activity in adipose tissue, likely mediated in part by lower beta-adrenergic receptor 3 (ADRB3) expression. Acute CR did not reverse these adipose changes but further reduced plasma free fatty acid (FA) levels by dampening lipolytic activity and upregulating oxidative pathways in muscle and liver. This facilitates insulin-stimulated glucose disposal and restores insulin sensitivity.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle, Liver, Epididymal White Adipose Tissue, Subcutaneous Adipose Tissue

SUBMITTER: Xiaowen Duan

LAB HEAD: David Savage

PROVIDER: PXD067874 | Pride | 2026-06-08

REPOSITORIES: Pride

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Publications

Integrated analysis of insulin resistance reveals metabolic remodeling following diet switch-triggered calorie reduction.

Duan Xiaowen X Davis Lucy M LM Patel Satish S Bidault Guillaume G Long Lu L Jenkins Benjamin B Yi Yao Y Pushpa Pushpa P Wesseling Julia R JR Koulman Albert A Vidal-Puig Antonio A Fazakerley Daniel J DJ Savage David B DB

Science advances 20260506 19

Insulin resistance (IR) links obesity to metabolic disorders. While weight loss reverses IR, we show that calorie reduction (CR) can do so in obese mice within a day before significant weight loss. In contrast to whole-body IR, individual tissues do not revert to their original chow diet-fed states after CR. In the liver, improved insulin sensitivity correlates with reduced triacylglycerol and diacylglycerol and protein kinase C epsilon activity, alongside substantially decreased de novo lipogen ...[more]

PMID: 42090498

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Project description:Development of insulin resistance is a key pathogenic component underlying metabolic syndrome and Type 2 diabetes (T2DM). Despite its importance, the molecular mechanisms underlying insulin resistance are poorly understood. Genome-wide association studies for T2DM and other metabolic traits have led to the identification of many candidate SNPs, but the majority of these SNPs are noncoding and determination of associated causal genes and/or specific tissue sites of action have been difficult. Adipocytes are critical regulators of mammalian metabolic homeostasis, with important effects on appetite, satiety, glucose and lipid homeostasis, energy expenditure, blood pressure, and immune function. Although insulin resistance (IR) in skeletal muscle, the major source of glucose disposal, is responsible for the bulk of the hyperglycemia observed in T2DM, muscle IR KO mice are generally healthy, IR also occurs in adipocytes, and inflammation within adipose tissue has been proposed as a primary mediator of IR, resulting in excess release of free fatty acids as well as alterations in adipokine release. Absence of adipose tissue, as observed in various lipodystrophies, or adipocyte-specific knockout of genes such as GLUT4 or insulin receptor, also alter systemic IR and T2DM risk. Transcriptional changes in adipocytes associated with metabolic disease. Despite the importance of adipocytes to metabolic disease, we have a poor understanding of how the adipocyte transcriptome changes in the disease state. Studies investigating transcriptional changes in whole adipose tissue have shown decreases in genes involved in adipogenesis, as well as alterations in inflammation, mitochondrial metabolism, lipid metabolism, detoxification, and insulin signaling. However, the vast majority of these studies use total adipose tissue samples, which does not allow for the exclusive evaluation of gene expression in mature adipocytes due to the substantial number of nonadipocyte cells (immune cells, fibroblasts, endothelial cells, pre-adipocytes, and mesenchymal cells) that also reside in adipose tissue. This is particularly relevant when studying metabolic disorders related to obesity-associated insulin resistance because these conditions are characterized by an increased influx of inflammatory cells into the adipose tissue.

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