Kennard, S. | bioRxiv Science

bioRxiv2025

Adipocyte Leptin Signaling Regulates Glycemia and Cardiovascular Function via Enhancing Brown Adipose Tissue Thermogenesis in Obese Male Mice.

While leptin control of metabolism is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin on systemic metabolism, especially in the context of obesity, remains unclear. To address this question, we selectively restored adipocyte leptin receptor (LEPR) expression in obese male and female LEPR conditional KO mice. Adipocyte LEPR restoration did not affect body weight but selectively increased brown adipose tissue (BAT) mass in male mice. This was associated with increased energy expenditure, smaller BAT adipocytes, lower triglycerides content, and increased markers of browning and lipolysis exclusively in males. Additionally, adipocyte LEPR restoration enhanced the expression of markers of endothelial cell and angiogenesis in male BAT, supporting increased local vascularization. Improved BAT function in males was also associated with lower HbA1c, better insulin sensitivity, reduced systolic blood pressure, decreased arterial stiffness and improved endothelial function. Lastly, adipocyte LEPR restoration lowered circulating pro-inflammatory cytokines and reduced tissue inflammation in the aorta and the heart, again in males only. These findings reveal a critical role for adipocyte leptin signaling in regulating BAT function and emphasize its importance in maintaining glycemic and cardiovascular health in males with obesity. Article HighlightsLeptin is known to enhance BAT activity through sympathetic stimulation. However, in vitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control, in obesity, remain ill-defined. We addressed this question by selectively restoring leptin receptor (LEPR) in adipocytes of obese LEPR conditional KO mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings revealed a crucial role for BAT leptin signaling in regulating energy expenditure, glycemic and cardiovascular health, primarily in males. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/681380v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@ed0b30org.highwire.dtl.DTLVardef@79ba56org.highwire.dtl.DTLVardef@1b86d93org.highwire.dtl.DTLVardef@1220a46_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Loss of Neurofibromin Induces Inflammatory Macrophage Phenotypic Switch and Retinal Neovascularization via GLUT1 Activation

Persons with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome, are largely protected from diabetes and exhibit evidence of enhanced glucose metabolism, which is replicated in mice harboring Nf1 mutations. A hallmark of NF1-associated neurofibromas and sarcomas is the high density of inflammatory macrophages and targeting macrophages appears efficacious in models of NF1. Inflammatory macrophages rely on glycolysis to rapidly generate ATP; thus, identifying whether neurofibromin, the protein encoded by the NF1 gene, controls glucose uptake and/or glycolysis in macrophages is therapeutically compelling. Using neurofibromin-deficient macrophages and macrophage-specific Nf1 knockout mice, we demonstrate that neurofibromin complexes with glucose transporter 1 (GLUT1) to restrain its activity and that loss of neurofibromin permits Akt2 to facilitate GLUT1 translocation to the membrane in macrophages. In turn, glucose internalization and glycolysis are highly up regulated and provoke putative reparative (M2) macrophages to undergo inflammatory phenotypic switch. Inflammatory M1 macrophages and inflammatory-like M2 macrophages invest the perivascular stroma of tumors and induce pathologic angiogenesis in mice harboring macrophage-specific Nf1 deletion. These studies identify a clear mechanism for the enhanced glycolysis and low risk for diabetes observed in persons with NF1 and provide a novel therapeutic target for manifestations of NF1.

cell biology↗