Biology subjects

Cavallari, J. F.

Publications and source records attributed to Cavallari, J. F..

4 recordsLinked to original sources

bioRxiv2025

Insulin Prevents Fat Loss and Promotes Muscle Loss During Intermittent Fasting in Obesity

Elevated blood glucose, insulin, and insulin resistance are associated with obesity and type 2 diabetes (T2D). High blood insulin levels blunt lipolysis and promote lipogenesis, and thus weight gain. Intermittent fasting (IF) has emerged as a weight loss strategy that also lowers blood glucose and improves insulin resistance. However, some people with obesity, or T2D have less fat loss and more lean mass loss after IF. It is not known why some people lose more fat or muscle during IF. We hypothesized that features of obesity, such as high insulin and insulin action in adipocytes dictate less adipose loss and more muscle loss during IF. In humans, we found that people living with obesity and higher blood insulin lost more lean mass after a 48-hour fast. Chronic elevation of insulin in obese mice lowered adipose loss and promoted muscle loss after 10 weeks of 5:2 IF in obese mice, while concurrently lowering adipose tissue interferon regulatory factor 4 (IRF4) expression. Whole-body and adipocyte-specific deletion of Irf4 in mice phenocopied chronic hyperinsulinemia, resulting in less fat loss and greater muscle loss after 10 weeks of 5:2 IF, which occurred in mouse models of equal and reduced caloric intake during IF. Therefore, hyperinsulinemia and suppression of adipocyte IRF4 promote muscle loss over fat loss during IF. Significance StatementIt is not known why some people lose muscle during IF. In humans, we found that high blood insulin during obesity correlated with increased lean mass loss after one 48-hour fast. Mechanistically, we found that hyperinsulinemia and the insulin responsive factor IRF4 within adipocytes as regulators of adipose and muscle loss during chronic IF obese mice. Therefore, insulin status and regulation of adipocyte IRF4 may be important factors to consider before prescribing IF for weight loss as lower muscle mass is known to be detrimental to metabolic and overall health status.

physiology↗

bioRxiv2021

Metabolic endotoxemia is dictated by the type of lipopolysaccharide

Lipopolysaccharides (LPS) can promote metabolic endotoxemia, which is considered inflammatory and metabolically detrimental based on Toll-like receptor (TLR)4 agonists such as Escherichia coli-derived LPS. LPS from certain bacteria antagonize TLR4 yet contribute to endotoxemia measured by Endotoxin Units (EU). We found that E. coli LPS impaired gut barrier function and worsened glycemic control in mice, but equal doses of LPS from other bacteria did not. Matching the LPS dose from R. sphaeroides and E. coli by EU revealed that only E. coli LPS promoted dysglycemia, adipose inflammation, delayed intestinal glucose absorption, and augmented insulin and GLP-1 secretion. Metabolically beneficial endotoxemia promoted by R. sphaeroides LPS counteracted dysglycemia caused by an equal dose of E. coli LPS and promoted insulin sensitivity in obese mice. The concept of metabolic endotoxemia should be expanded beyond LPS load (EU) to include LPS characteristics, where the balance of deleterious and beneficial endotoxemia regulates host metabolism. HighlightsO_LIType of LPS dictates gut barrier function, inflammation, insulin, GLP-1, intestinal glucose absorption and blood glucose C_LIO_LIEndotoxin Units (EU) do not reflect how LPS influences blood glucose or hormones C_LIO_LILPS derived from certain types of bacteria are insulin sensitizers C_LIO_LIR. sphaeroides LPS promotes metabolically beneficial endotoxemia C_LIO_LILPS characteristics dictate metabolically beneficial versus deleterious endotoxemia C_LI

physiology↗

bioRxiv2020

Gut microbiota impairs insulin clearance during obesity

Hyperinsulinemia can be a cause and consequence of obesity and insulin resistance. Increased insulin secretion and reduced insulin clearance can contribute to hyperinsulinemia. The triggers for changes in insulin clearance during obesity are ill-defined. We found that oral antibiotics mitigated impaired insulin clearance in mice fed a high fat diet (HFD) for 12 weeks or longer. Short-term HFD feeding and aging did not alter insulin clearance in mice. Germ-free mice colonized with microbes from HFD-fed mice had impaired insulin clearance, but not C-peptide clearance, and only after mice were colonized for 6 weeks and then HFD-fed. Five bacterial taxa predicted >90% of the variance in insulin clearance. Our data indicate that gut microbes are an independent and transmissible factor that regulates obesity-induced changes in insulin clearance. A small cluster of microbes may be a target for mitigating defects in insulin clearance and the progression of obesity and Type 2 Diabetes. We propose that a small community in the gut microbiota can impair insulin clearance and increase insulin load and the risk of complications from hyperinsulinemia.

physiology↗

bioRxiv2020

RIPK2 dictates insulin responses to tyrosine kinase inhibitors in obese mice

Tyrosine kinase inhibitors (TKIs) used in cancer are also being investigated in diabetes. TKIs can improve blood glucose control in diabetic cancer patients, but the specific kinases that alter blood glucose or insulin are not clear. We sought to define the role of Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) in mouse models of insulin resistance. We tested the TKI gefitinib, which inhibits RIPK2 activity, in WT, Nod1-/-, Nod2-/- and Ripk2-/- mice fed an obesogenic high fat diet. Gefitinib lowered blood glucose during a glucose tolerance test (GTT) in a NOD-RIPK2-independent manner in all obese mice. However, gefitinib lowered glucose-stimulated insulin secretion only in obese Ripk2-/- mice. Gefitinib had no effect on insulin secretion in obese WT, Nodi-/-, or Nod2-/- mice. Hence, genetic deletion of Ripk2 promoted the insulin sensitizing potential of gefitinib, since this TKI lowered both blood glucose and insulin only in Ripk2-/- mice. Gefitinib did not alter the inflammatory profile of pancreas, adipose, liver or muscle tissues in obese Ripk2-/- mice compared to obese WT mice. We also tested imatinib, a TKI which does not inhibit RIPK2 activity, in obese WT mice. Imatinib lowered blood glucose during a GTT, consistent with TKIs lowering blood glucose independently of RIPK2. However, imatinib increased glucose-stimulated insulin secretion during the glucose challenge. These data show that multiple TKIs lower blood glucose, where actions of TKIs on RIPK2 dictate divergent insulin responses, independent of tissue inflammation. Our data shows that RIPK2 limits the insulin sensitizing effect of gefitinib, whereas imatinib increased insulin secretion.

physiology↗