Adipocyte Ceramides Regulate Subcutaneous Adipose Browning, Inflammation, and Metabolism

Abstract

Adipocytes package incoming fatty acids into triglycerides and other glycerolipids, with only a fraction spilling into a parallel biosynthetic pathway that produces sphingolipids. Herein, we demonstrate that subcutaneous adipose tissue of type 2 diabetics contains considerably more sphingolipids than non-diabetic, BMI-matched counterparts. Whole-body and adipose tissue-specific inhibition/deletion of serine palmitoyltransferase (Sptlc), the first enzyme in the sphingolipid biosynthesis cascade, in mice markedly altered adipose morphology and metabolism, particularly in subcutaneous adipose tissue. The reduction in adipose sphingolipids increased brown and beige/brite adipocyte numbers, mitochondrial activity, and insulin sensitivity. The manipulation also increased numbers of anti-inflammatory M2 macrophages in the adipose bed and induced secretion of insulin-sensitizing adipokines. By comparison, deletion of serine palmitoyltransferase from macrophages had no discernible effects on metabolic homeostasis or adipose function. These data indicate that newly synthesized adipocyte sphingolipids are nutrient signals that drive changes in the adipose phenotype to influence whole-body energy expenditure and nutrient metabolism.

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

“…However, the relative contribution of adiposity versus ceramides on insulin resistance was not addressed in this study. In other studies, ceramides were significantly elevated in SAT of obese diabetic as compared to obese nondiabetic individuals (42, 71) while ceramide content of VAT did not differ between these groups (71). More direct evidence of a role for ceramide in glucose homeostasis has been generated from several murine studies of altered ceramide metabolism (71, 150, 183, 384, 476, 522).…”

“…More direct evidence of a role for ceramide in glucose homeostasis has been generated from several murine studies of altered ceramide metabolism (71, 150, 183, 384, 476, 522). Phenotypes of mice with reduced ceramide synthesis or increased ceramide catabolism are consistently characterized by improved glucose tolerance and insulin sensitivity (71, 150, 183, 476, 522). …”

Macrophage functions in lean and obese adipose tissue

“…Ceramides activate the NLRP3 inflammasome. Whole body and adipocyte-specific depletion of ceramides in mice by inhibiting their synthesis by serine palmitoyltransferase induces adipose tissue browning and increases M2 macrophages 139 . Ablation of NLRP3 in mice improves insulin sensitivity, reduces IL-18, and reduces effector T cells in adipose tissue 140 .…”

Lipid-mediated signals that regulate mitochondrial biology

“…Another study demonstrated increased mitochondrial biogenesis and beta-oxidative capacity in brown adipocytes upon CerS6 deletion (31). Increased ETC activity has also been observed in adipocytes lacking serine palmitoyltransferase, an enzyme required for the synthesis of ceramide precursors (32). Although these experiments provide compelling evidence for a role for ceramides in modulating ETC activity, the mechanisms through which this occurs are unclear.…”