Biology subjects

Barra, N. G.

Publications and source records attributed to Barra, N. G..

5 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

Gut microbiota-based vaccination engages innate immunity to improve blood glucose control in obese mice

Obesity and diabetes increase circulating levels of microbial components derived from the gut microbiota. Individual bacterial factors (i.e., postbiotics) can have opposing effects on metabolic inflammation and blood glucose control. We tested the net effect of gut bacterial extracts on blood glucose using a microbiota-based vaccination strategy in mice. Male and female mice had improved insulin sensitivity and blood glucose control five weeks after a single subcutaneous injection of a specific dose of a bacterial extract obtained from the luminal contents of the proximal gut. Injection of mice with proximal gut extracts from germ-free mice revealed that bacteria were required for a microbiota-based vaccination to improve blood glucose control. Vaccination of Nod1-/-, Nod2-/-, and Ripk2-/- mice showed that each of these innate immune proteins was required for bacterial extract injection to improve blood glucose control. A microbiota-based vaccination promoted a proximal gut immunoglobulin-G (IgG) response directed against bacterial extract antigens, where subcutaneous injection of mice with the luminal contents of the ileum elicited a bacterial extract-specific IgG response that is compartmentalized to the ileum of vaccinated mice. A microbiota-based vaccination was associated with an altered the microbiota composition in the ileum and colon of mice. Lean mice required a single injection of proximal gut bacterial extracts, but high fat diet (HFD)-fed, obese mice required prime-boost bacterial extract injections for improvements in blood glucose control. These data show that, upon subversion of the gut barrier, vaccination with proximal gut bacterial extracts engages innate immunity to promote long-lasting improvements in blood glucose control in a dose-dependent manner.

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

Inflammation promotes adipocyte lipolysis via IRE1 kinase

Obesity associates with inflammation, insulin resistance and higher blood lipids. It is unclear if immune responses facilitate lipolysis separate from hormone or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis regulated by adrenergic or hormonal stimuli. Inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. Adipocyte-specific deletion of IRE1 in mice prevented inflammatory ligand-induced lipolysis in adipose tissue. IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. We found no role for canonical unfolded protein responses (UPR) or ABL kinases in linking ER stress to lipolysis. Lipolysis was unchanged in adipose tissue from GRP78/BiP+/- compared to littermate mice. Tyrosine kinase inhibitors (TKIs) such as imatinib, which reduce ER stress and IRE1 RNase activity, did not alter lipolysis from inflammatory stimuli. Inhibiting IRE1 kinase activity blocked adipocyte NF-{kappa}B activation and Interleukin-6 (Il6) production due to inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signalling in adipocytes. Therefore, inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. Our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation, including insulin resistance. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders. SignificanceAdipocytes maintain metabolic homeostasis by storing nutrients and releasing lipids into the blood via lipolysis. Catecholamines stimulate adrenergic-mediated lipolysis, whereas insulin inhibits lipolysis. Obesity is associated with elevated blood lipids and inflammation, which can impair insulin-mediated suppression of lipolysis (i.e. insulin resistance). It is unclear if inflammatory triggers of lipolysis require insulin resistance or if specific lipolytic triggers engage distinct cell stress components. We found that a specific ER stress response was required for inflammation-mediated lipolysis, not adrenergic-mediated lipolysis. Bacterial and cytokine-induced lipolysis required adipocyte IRE1 kinase activity, but not IRE1 RNase activity typical of the ER stress-related unfolded protein response. We propose that inflammatory triggers of lipolysis engage IRE1 kinase independent of catecholamine and hormone responses, including insulin resistance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/030148v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@c9ae43org.highwire.dtl.DTLVardef@cfb430org.highwire.dtl.DTLVardef@3ecd2aorg.highwire.dtl.DTLVardef@10fbafe_HPS_FORMAT_FIGEXP M_FIG C_FIG IRE1 kinase activity promotes an inflammation-specific adipocyte lipolytic program that is separate from hormonal or adrenergic regulation of lipolysis.

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↗