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.
Highlights
Obesity and its associated co-morbidities are among the most problematic health conditions modern societies have to deal with [1]
In order to more clearly understand the role of Gal-3 in obesity and its associated metabolic and inflammatory consequences, in the present study we investigated the effect of Gal-3 deficiency using the model of high fat diet (HFD)-induced obesity (DIO) in mice
The increased fat mass of Gal-3 KO mice was confirmed by significantly higher levels of circulating leptin in 20-week-old Lean and Diet-induced Obese (DIO) Gal-3 KO mice compared to their respective WT groups (Fig. 1D)
Summary
Obesity and its associated co-morbidities are among the most problematic health conditions modern societies have to deal with [1]. Individual differences in the degree of adiposity, the immune and inflammatory response, the ability of the organism to handle oxidative stress as well as composition of the gut microbiota are important factors in the development of obesity-associated comorbidities [2]. Gal-3 KO mice subjected to dietinduced atherosclerosis or diabetes-associated kidney damage experience increased oxidative stress and inflammatory responses, leading to more severe pathology [5,6,7,8]. Controversial results have been published on the effect of Gal-3 deficiency in models of hepatic steatosis/inflammation, with studies indicating either protection or increased disease severity in Gal-3 KO mice [9,11,12]. There is agreement that Gal-3 KO mice demonstrate elevated hepatic expression of peroxisome-proliferator-activated receptor c (PPARc), suggesting that Gal-3 participates in the regulation of fatty acid and glucose metabolism in the liver [9,12]
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