Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice

Abstract

Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6Chigh monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

“…Data on galectin-3 inhibition are not univocal, however, and galectin-3 deletion exacerbates systemic inflammation, hyperglycemia, and liver and kidney injury in diet-induced obese rodents (88). It has been suggested that inhibition of AGE uptake by the liver, which clears .90% of these end products from the circulation, promotes the systemic accumulation of AGEs and receptor for AGE (RAGE)-mediated uptake by other tissues, thereby aggravating extrahepatic toxicity of these molecules.…”

Galectin-3 in diabetic patients

“…Two independent research laboratories investigated the role of galectin-3 in the modulation of metabolic disorders induced by an obesogenic HFD containing 60% calories from saturated fat [92,93]. Both studies demonstrated a protective role of galectin-3 toward obesity and type 2 diabetes, via modulation of the responsiveness of innate and adaptive immunity to overnutrition [92,93].…”

Galectin-3 Deletion Enhances Visceral Adipose Tissue Inflammation and Dysregulates Glucose Metabolism in Mice on a High-Fat Diet

“…Additionally, Pejnovic et al (18) reported significantly increased IFN-γ-producing Type 1 T/NKT cells and proinflammatory M1 macrophages and reduced T regulatory cells and alternatively activated M2 macrophages in the VAT of LGALS3 -/-mice fed a HFD compared with diet-matched WT animals. Pang et al (27) reported that Gal-3-deficient mice fed a HFD for 12 weeks develop increased adiposity and systemic inflammation. In addition, the same authors showed that despite the increased adiposity in Gal-3-deficient mice, there was no significant difference in the size of the adipocytes (27).…”

“…Pang et al (27) reported that Gal-3-deficient mice fed a HFD for 12 weeks develop increased adiposity and systemic inflammation. In addition, the same authors showed that despite the increased adiposity in Gal-3-deficient mice, there was no significant difference in the size of the adipocytes (27). In this study, we demonstrated that LGALS3-/-mice fed a HFD for 6 months developed visceral adiposity, hyperglycaemia and IR.…”

“…On the other hand, Pejnovic et al reported that obese Gal-3-deficient mice had enhanced adiposity, hyperglycaemia, hyperinsulinemia, IR and systemic inflammation in comparison with their diet-matched wild-type controls (18). Moreover, in a study by Peng et al (27), Gal-3-null mice fed a HFD had increased adiposity and dysregulated glucose metabolism. In addition, the same authors found that young Gal-3-deficient mice fed a standard diet exhibit altered glucose homeostasis, thus suggesting the modulation of glucose metabolism and possibly β-cell function by Galectin-3 (Gal-3) independently of obesity and inflammation.…”