CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice.

AIMS/HYPOTHESIS: Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition. METHODS: We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet. RESULTS: CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1ß+ islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1ß as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1ß prior to glucose stimulation in mice lacking macrophages. CONCLUSIONS/INTERPRETATION: Macrophages and macrophage-derived factors, such as IL-1ß, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease. DATA AVAILABILITY: The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 ).

Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing.

Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neurotransmitters and hormones. PC1/3 deficiency and genome-wide association studies relate PC1/3 with early onset obesity. Here, we find that deletion of PC1/3 in obesity-related neuronal cells expressing proopiomelanocortin mildly and transiently change body weight and fail to produce a phenotype when targeted to Agouti-related peptide- or nestin-expressing tissues. In contrast, pancreatic ß cell-specific PC1/3 ablation induces hyperphagia with consecutive obesity despite uncontrolled diabetes with glucosuria. Obesity develops not due to impaired pro-islet amyloid polypeptide processing but due to impaired insulin maturation. Proinsulin crosses the blood-brain-barrier but does not induce central satiety. Accordingly, insulin therapy prevents hyperphagia. Further, islet PC1/3 expression levels negatively correlate with body mass index in humans. In this work, we show that impaired PC1/3-mediated proinsulin processing, as observed in human prediabetes, promotes hyperphagic obesity.

Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity.

The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.

Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1ß.

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1ß leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1ß in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

Distinct Transcriptional Responses across Tissue-Resident Macrophages to Short-Term and Long-Term Metabolic Challenge.

The innate immune system safeguards the organism from both pathogenic and environmental stressors. Also, physiologic levels of nutrients affect organismal and intra-cellular metabolism and challenge the immune system. In the long term, over-nutrition leads to low-grade systemic inflammation. Here, we investigate tissue-resident components of the innate immune system (macrophages) and their response to short- and long-term nutritional challenges. We analyze the transcriptomes of six tissue-resident macrophage populations upon acute feeding and identify adipose tissue macrophages and the IL-1 pathway as early sensors of metabolic changes. Furthermore, by comparing functional responses between macrophage subtypes, we propose a regulatory, anti-inflammatory role of heat shock proteins of the HSP70 family in response to long- and short-term metabolic challenges. Our data provide a resource for assessing the impact of nutrition and over-nutrition on the spectrum of macrophages across tissues with a potential for identification of systemic responses.