Enhanced Fatty Acid Flux Triggered by Adiponectin Overexpression

Abstract

Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

“…Liver triglyceride content did not correlate with serum triglyceride levels in APNko-DHT mice, while APNtg mice had lower circulating triglycerides. There may be multiple protective effects of adiponectin on hepatic steatosis and hypertriglyceridemia, including direct action on the liver, improved capacity for safe deposition of excess nutrients in the s.c. fat compartment, and an increased metabolic activity in BAT (16,17,(42)(43)(44).…”

“…In contrast, BAT mRNA levels of several mitochondrial markers were decreased in APNtg mice. Nevertheless, BAT in APNtg mice appears very active, with a fivefold greater triglyceride synthesis and turnover compared with littermate WT controls (42) −ΔCt ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 for the effect of DHT within genotypes; † P < 0.05, † † P < 0.01, † † † P < 0.001 for the effect of DHT between genotypes, n = 7-8/group.…”

“…ages (42). Thus, the gene expression pattern may not always reflect BAT functionality, and further research is needed to investigate the role of BAT in this PCOS model.…”

Adiponectin: mechanistic insights and clinical implications

“…Similarly, studies in humans have consistently shown an association between low adiponectin levels and the presence and degree of liver fat [54]. Transgenic mice overexpressing Adipoq show reduced lipogenic activity at the level of the liver [55], but may be predominantly protected as a result of a healthy, non-inflamed expansion of adipose tissue that can readily accommodate any excess lipids [52,53].…”

A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation

“…Remarkably, we did not observe an induction of DNL after 1 d of T0901317 treatment, whereas hepatic TG content and lipogenic gene expression were already significantly elevated and accompanied by an enhanced secretion of VLDL-TG. Research in experimental animals (33,41,42) and human subjects (43,44) has shown that physiologic pathways other than DNL also contribute to hepatic TG (43). An increase in hepatic content of the dietary and/or adipose-derived essential fatty acid linoleate after 1 d of treatment indeed indicated a shift in the balance between hepatic fatty acid import and export.…”