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Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation

The deleterious effect of chronic activation of the IL-1β system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1β in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1β, in a glucose-dependent manner. Subsequently, IL-1β contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1β signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1β and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1β mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium–glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1β and insulin in the regulation of both metabolism and immunity.

Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance

High-fat feeding for 3-4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.

Mesenteric Fat Lipolysis Mediates Obesity-associated Hepatic Steatosis and Insulin Resistance

Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin’s ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet–induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = −0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.

Induction of Cytosolic Phospholipase A2α Is Required for Adipose Neutrophil Infiltration and Hepatic Insulin Resistance Early in the Course of High-Fat Feeding

In established obesity, inflammation and macrophage recruitment likely contribute to the development of insulin resistance. In the current study, we set out to explore whether adipose tissue infiltration by neutrophils that occurs early (3 days) after initiating a high-fat diet (HFD) could contribute to the early occurrence of hepatic insulin resistance and to determine the role of cytosolic phospholipase A2α (cPLA2α) in this process. The 3-day HFD caused a significant upregulation of cPLA2α in periepididymal fat and in the liver. A specific antisense oligonucleotide (AS) effectively prevented cPLA2α induction, neutrophil infiltration into adipose tissue (likely involving MIP-2), and protected against 3-day HFD–induced impairment in hepatic insulin signaling and glucose over-production from pyruvate. To sort out the role of adipose neutrophil infiltration independent of cPLA2α induction in the liver, mice were injected intraperitoneally with anti–intracellular adhesion molecule-1 (ICAM-1) antibodies. This effectively prevented neutrophil infiltration without affecting cPLA2α or MIP-2, but like AS, prevented impairment in hepatic insulin signaling, the enhanced pyruvate-to-glucose flux, and the impaired insulin-mediated suppression of hepatic glucose production (assessed by clamp), which were induced by the 3-day HFD. Adipose tissue secretion of tumor necrosis factor-α (TNF-α) was increased by the 3-day HFD, but not if mice were treated with AS or ICAM-1 antibodies. Moreover, systemic TNF-α neutralization prevented 3-day HFD–induced hepatic insulin resistance, suggesting its mediatory role. We propose that an acute, cPLA2α-dependent, neutrophil-dominated inflammatory response of adipose tissue contributes to hepatic insulin resistance and glucose overproduction in the early adaptation to high-fat feeding.

Interleukin-6 contributes to early fasting-induced free fatty acid mobilization in mice

Contracting muscle releases interleukin-6 (IL-6) enabling the metabolic switch from carbohydrate to fat utilization. Similarly, metabolism is switched during transition from fed to fasting state. Herein, we examined a putative role for IL-6 in the metabolic adaptation to normal fasting. In lean C57BL/6J mice, 6 h of food withdrawal increased gene transcription levels of IL-6 in skeletal muscle but not in white adipose tissue. Concomitantly, circulating IL-6 and free fatty acid (FFA) levels were significantly increased, whereas respiratory quotient (RQ) was reduced in 6-h fasted mice. In white adipose tissue, phosphorylation of hormone-sensitive lipase (HSL) was increased on fasting, indicating increased lipolysis. Intriguingly, fasting-induced increase in circulating IL-6 levels and parallel rise in FFA concentration were absent in obese and glucose-intolerant mice. A causative role for IL-6 in the physiological adaptation to fasting was further supported by the fact that fasting-induced increase in circulating FFA levels was significantly blunted in lean IL-6 knockout (KO) and lean C57BL/6J mice treated with neutralizing IL-6 antibody. Consistently, phosphorylation of HSL was significantly reduced in adipose tissue of IL-6-depleted mice. Hence, our findings suggest a novel role for IL-6 in energy supply during early fasting.

From signal transduction to signal interpretation: An alternative model for the molecular function of insulin receptor substrates

The insulin receptor (IR) recruits adaptor proteins, so-called insulin receptor substrates (IRS), to connect with downstream signalling pathways. A family of IRS proteins was defined based on three major common structural elements: Amino-terminal PH and PTB domains that mediate protein-lipid or protein-protein interactions, mostly carboxy-terminal multiple tyrosine residues that serve as binding sites for proteins that contain one or more SH2 domains and serine/threonine-rich regions which may be recognized by negative regulators of insulin action. The current model for the role of IRS proteins therefore combines an adaptor function with the integration of mostly negative input from other signal transduction cascades allowing for modulation of signalling amplitude. In this review we propose an extended version of the adaptor model that can explain how signalling specificity could be implemented at the level of IRS proteins.

Fas (CD95) expression in myeloid cells promotes obesity‐induced muscle insulin resistance.

Low‐grade inflammation in adipose tissue and liver has been implicated in obesity‐associated insulin resistance and type 2 diabetes. Yet, the contribution of inflammatory cells to the pathogenesis of skeletal muscle insulin resistance remains elusive. In a large cohort of obese human individuals, blood monocyte Fas (CD95) expression correlated with systemic and skeletal muscle insulin resistance. To test a causal role for myeloid cell Fas expression in the development of skeletal muscle insulin resistance, we generated myeloid/haematopoietic cell‐specific Fas‐depleted mice. Myeloid/haematopoietic Fas deficiency prevented the development of glucose intolerance in high fat‐fed mice, in ob/ob mice, and in mice acutely challenged by LPS. In vivo, ex vivo and in vitro studies demonstrated preservation of muscle insulin responsiveness with no effect on adipose tissue or liver. Studies using neutralizing antibodies demonstrated a role for TNFα as mediator between myeloid Fas and skeletal muscle insulin resistance, supported by significant correlations between monocyte Fas expression and circulating TNFα in humans. In conclusion, our results demonstrate an unanticipated crosstalk between myeloid cells and skeletal muscle in the development of obesity‐associated insulin resistance.

Short-term HFD does not alter lipolytic function of adipocytes

A short bout of high fat diet (HFD) impairs glucose tolerance and hepatic insulin sensitivity. We recently identified adipose tissue inflammation and resulting dysfunctional adipose tissue–liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance. In particular, reducing white adipose tissue (WAT) inflammation by adipocyte-specific depletion of Fas/CD95 protected mice from developing hepatic insulin resistance but not hepatic steatosis. Herein, we expanded our previous work and determined the impact of four days of HFD on lipolytic activity of isolated adipocytes. Compared with chow-fed mice, the degree of basal and isoproterenol-stimulated free fatty acid (FFA) and glycerol release was similar in HFD-fed animals. Moreover, insulin’s ability to suppress lipolysis remained intact, suggesting retained insulin sensitivity. Despite unaltered lipolysis, circulating FFA concentrations were greatly increased in non-fasted HFD-fed mice. In conclusion, a short-term HFD challenge does not affect lipolytic function of adipocytes. The observed increase of circulating FFA levels in randomly fed animals may rather be the result of increased dietary fat supply.

IL-6-type Cytokine Signaling in Adipocytes Induces Intestinal GLP-1 Secretion

We recently showed that interleukin (IL)-6–type cytokine signaling in adipocytes induces free fatty acid release from visceral adipocytes, thereby promoting obesity-induced hepatic insulin resistance and steatosis. In addition, IL-6–type cytokines may increase the release of leptin from adipocytes and by those means induce glucagon-like peptide 1 (GLP-1) secretion. We thus hypothesized that IL-6–type cytokine signaling in adipocytes may regulate insulin secretion. To this end, mice with adipocyte-specific knockout of gp130, the signal transducer protein of IL-6, were fed a high-fat diet for 12 weeks. Compared with control littermates, knockout mice showed impaired glucose tolerance and circulating leptin, GLP-1, and insulin levels were reduced. In line, leptin release from isolated adipocytes was reduced, and intestinal proprotein convertase subtilisin/kexin type 1 (Pcsk1) expression, the gene encoding PC1/3, which controls GLP-1 production, was decreased in knockout mice. Importantly, treatment with the GLP-1 receptor antagonist exendin 9–39 abolished the observed difference in glucose tolerance between control and knockout mice. Ex vivo, supernatant collected from isolated adipocytes of gp130 knockout mice blunted Pcsk1 expression and GLP-1 release from GLUTag cells. In contrast, glucose- and GLP-1–stimulated insulin secretion was not affected in islets of knockout mice. In conclusion, adipocyte-specific IL-6 signaling induces intestinal GLP-1 release to enhance insulin secretion, thereby counteracting insulin resistance in obesity.

Opposing effects of reduced kidney mass on liver and skeletal muscle insulin sensitivity in obese mice

Reduced kidney mass and/or function may result in multiple metabolic derangements, including insulin resistance. However, underlying mechanisms are poorly understood. Herein, we aimed to determine the impact of reduced kidney mass on glucose metabolism in lean and obese mice. To that end, 7-week-old C57BL/6J mice underwent uninephrectomy (UniNx) or sham operation. After surgery, animals were fed either a chow (standard) diet or a high-fat diet (HFD), and glucose homeostasis was assessed 20 weeks after surgery. Intraperitoneal glucose tolerance was similar in sham-operated and UniNx mice. However, insulin-stimulated glucose disposal in vivo was significantly diminished in UniNx mice, whereas insulin-stimulated glucose uptake into isolated skeletal muscle was similar in sham-operated and UniNx mice. Of note, capillary density was significantly reduced in skeletal muscle of HFD-fed UniNx mice. In contrast, hepatic insulin sensitivity was improved in UniNx mice. Furthermore, adipose tissue hypoxia-inducible factor 1α expression and inflammation were reduced in HFD-fed UniNx mice. Treatment with the angiotensin II receptor blocker telmisartan improved glucose tolerance and hepatic insulin sensitivity in HFD-fed sham-operated but not UniNx mice. In conclusion, UniNx protects from obesity-induced adipose tissue inflammation and hepatic insulin resistance, but it reduces muscle capillary density and, thus, deteriorates HFD-induced skeletal muscle glucose disposal.