SUMMARY Obesity activates a complex systemic immune response that includes the recruitment of macrophages and other immune cells to key metabolic tissues. Current models postulate that obesity and excess lipids classically activate macrophages, polarizing them toward an M1 (inflammatory) state. Little is known about noninflammatory functions of adipose tissue macrophages (ATMs). Here, we show that the expansion of adipose tissue (AT) across models of obesity induces a program of lysosome biogenesis in ATMs and is associated with lipid catabolism but not a classic inflammatory phenotype. This program is induced by factors produced by AT and is tightly coupled to lipid accumulation by ATMs. Inhibition of ATM lysosome function impairs lipid metabolism and increases lipid content in ATMs and reduces whole AT lipolysis. These data argue that ATMs contribute quantitatively to the development of obesity-induced inflammation but also serve an important role in lipid trafficking independent of their inflammatory phenotype.

To meet systemic metabolic needs, adipocytes release fatty acids and glycerol through the action of neutral lipases. Here, we describe a secondary pathway of lipid release from adipocytes that is independent of canonical lipolysis. We found that adipocytes release exosome-sized, lipid-filled vesicles (AdExos) that become a source of lipid for local macrophages. Adipose tissue from lean mice released ~1% of its lipid content per day via exosomes ex vivo, a rate that more than doubles in obese animals. AdExos and associated factors were sufficient to induce in vitro differentiation of bone marrow precursors into adipose tissue macrophage–like cells. Thus, AdExos are both an alternative pathway of local lipid release and a mechanism by which parenchymal cells can modulate tissue macrophage differentiation and function.

Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic b-cells of adult mice. atRA signaling was ablated in b-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-a mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in b-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge. Glucose-stimulated insulin secretion was also impaired in islets isolated from mice expressing RARdn. Among genes that are atRA responsive, Glut2 and Gck mRNA levels were decreased in isolated islets from RARdn-expressing mice. Histologic analyses of RARdn-expressing pancreata revealed a decrease in b-cell mass and insulin per b-cell 1 mo after induction of the RARdn. Our results indicate that atRA signaling mediated by RARs is required in the adult pancreas for maintaining both b-cell function and mass, and provide insights into molecular mechanisms underlying these actions.-Brun, P.-J., Grijalva, A., Rausch, R., Watson, E., Yuen, J. J., Das, B. C., Shudo, K., Kagechika, H., Leibel, R. L., Blaner, W. S. Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and b-cell mass. FASEB J. 29, 671-683 (2015). www.fasebj.orgHUMANS AND OTHER VERTEBRATES must acquire retinoids (vitamin A and its metabolites) from the diet in order to maintain normal health (1). Retinoids regulate many cellular processes including cellular proliferation, differentiation, and apoptosis, and hence, they have roles in many essential physiologic processes including the maintenance of immunity, reproduction, and embryonic development (2, 3). These essential actions are thought to be mediated primarily by the all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9cRA), which regulate transcription by serving as ligands for nuclear hormone receptors (4, 5). atRA serves as the natural ligand for the 3 retinoic acid receptors (RARs; a, b, and g); whereas 9cRA is proposed to be a natural ligand for the 3 retinoid X receptors (RXRs; a, b, and g) (6). Over 500 genes are reported to be responsive to either atRA or 9cRA (7).An extensive literature supports a role for retinoids in the maintenance of pancreatic endocrine functions (8-18). Pancreatic islets express genes encoding retinoland retinoic acid-binding proteins, as well as RARs and RXRs (14,19,20). Isolated pancreatic islets from rats fed a vitamin A-deficient diet display a markedly diminished capacity to secrete insulin in response to a glucose challenge (10). This phenotype was reversed by administering either retinyl ester or atRA to the rats prior to islet isolation. Two recent reports have identified a function for 9cRA and RXR signaling in the regulation of insulin secretion. Using an inducible dominant-ne...

Adipose tissue (AT) macrophages (ATMs) contribute to obesity-induced inflammation and metabolic dysfunction, but also play critical roles in maintaining tissue homeostasis. ATMs catabolize lipid in a lysosomal-dependent manner required for the maintenance of AT; deficiency in lysosomal acid lipase (Lipa), the enzyme required for lysosome lipid catabolism, leads to AT atrophy and severe hepatic steatosis, phenotypes rescued by macrophage-specific expression of Lipa. Autophagy delivers cellular products, including lipid droplets, to lysosomes. Given that obesity increases autophagy in AT and contributes to lipid catabolism in other cells, it was proposed that autophagy delivers lipid to lysosomes in ATMs and is required for AT homeostasis. We found that obesity does increase autophagy in ATMs. However, genetic or pharmacological inhibition of autophagy does not alter the lipid balance of ATMs in vitro or in vivo. In contrast to the deficiency of lysosomal lipid hydrolysis, the ablation of autophagy in macrophages does not lead to AT atrophy or alter metabolic phenotypes in lean or obese animals. Although the lysosomal catabolism of lipid is necessary for normal ATM function and AT homeostasis, delivery of lipid to lysosomes is not autophagy dependent and strongly suggests the existence of another lipid delivery pathway critical to lysosome triglyceride hydrolysis in ATMs.

Introduction This study compared basal analog (BA: glargine U100/mL and detemir) and premix (PM: human, lispro and aspart biphasic) insulin regimens in terms of their efficacy and safety in type 2 diabetes mellitus patients. Methods Searches of MEDLINE, Embase, and CENTRAL identified primary randomized controlled trials (RCTs) ≥ 12 weeks in duration that compared BA or PM insulin regimens in adults with T2DM, with ≥ 30 patients per arm. A systematic literature review and a pairwise meta-analysis were performed using a random effects model adjusted for between-study variability. Analyses were conducted based on frequency of bolus insulin and PM injections, PM ratio and type, BA type, race, follow-up period, and baseline glycosylated hemoglobin (HbA1c). Results Twenty-two primary RCTs with 9691 patients were included. The BA and PM regimens yielded similar changes in HbA1c and postprandial glucose levels, with a statistically significant reduction in fasting glucose [mean difference (MD) − 0.61 mmol/L (95% confidence interval (CI) − 0.90, − 0.32), I 2 = 89.6%]. The BA regimens showed significantly reduced rates of total hypoglycemia [odds ratio (OR) 0.77 (95% CI 0.64, 0.92), I 2 = 65.3%] and changes in body weight [MD − 0.48 kg (95% CI − 0.86, − 0.11), I 2 = 75.7%] compared to PM regimens. Stratification by PM type and dosing ratio demonstrated statistically significant reductions in HbA1c favoring BA compared to human [MD − 0.39% (95% CI − 0.60, − 0.18), I 2 = 61.8%] or 50/50-ratio [MD − 0.22% (95% CI − 0.40, − 0.04), I 2 = 0.0%] PM regimens. Other subgroup analyses found no difference in HbA1c change between the BA and PM regimens. Conclusion When compared to PM regimens, BA regimens yielded similar efficacies and better safety profiles in patients with type 2 diabetes mellitus. Funding Sanofi (Shanghai, China). Electronic supplementary material The online version of this article (10.1007/s13300-019-0606-6) contains supplementary material, which is available to authorized users.