Transgenic Mice Overexpressing SREBP-1a in Male ob/ob Mice Exhibit Lipodystrophy and Exacerbate Insulin Resistance

Abstract

Sterol regulatory element-binding protein (SREBP)-1a is a key transcription factor that activates the expression of genes involved in the synthesis of fatty acids, triglycerides (TGs), and cholesterol. Transgenic mice that overexpress the nuclear form of SREBP-1a under the control of the phosphoenolpyruvate carboxykinase promoter (Tg-1a) were previously shown to display a lipodystrophic phenotype characterized by enlarged and fatty livers, diminished peripheral white adipose tissue (WAT), and insulin resistance. In the current study, we crossed these Tg-1a mice with genetically obese (ob/ob) mice (Tg-1a;ob/ob) and examined change in fat distribution between liver and adipose tissues in severe obesity and mechanism underlying the lipodystrophic phenotype in mice with Tg-1a. Tg-1a;ob/ob mice developed more severe steatohepatitis but had reduced WAT mass and body weight compared with ob/ob mice. The reduction of WAT mass in Tg-1a and Tg-1a;ob/ob mice was accompanied by enhanced lipogenesis and lipid uptake in the liver, reduced plasma lipid levels, impaired adipocyte differentiation, reduced food intake, enhanced energy expenditure, and extended macrophage infiltration and fibrosis in WAT. Despite the improved glucose tolerance, Tg-1a;ob/ob mice showed severe peripheral insulin resistance. Adenoviral hepatic expression of SREBP-1a mimicked these phenotypes. The "fat steal"-like lipodystrophy phenotype of the Tg-1a;ob/ob model demonstrates that hepatic SREBP-1a activation has a strong impact on the partition of TG accumulation, resulting in adipose-tissue remodeling by inflammation and fibrosis and insulin resistance.

The impact of endotrophin on the progression of chronic liver disease

“…We subsequently measured total cholesterol and NEFA levels. Consistent with a previous report 25,26 , the levels were decreased in the S1a/Ctrl mice and were not significantly different compared to those in the S1a/ETP animals (Fig. 1o, p).…”

“…We examined whether the expression of ETP with nSREBP1a affects the lipid profiles in the serum. Consistent with previous reports, the levels of TG, NEFA, and total cholesterol in the S1a group were reduced compared to those in the control group 25,26 . Further, serum NEFAs in the S1a/ETP mice were slightly higher than those in the S1a mice alone, but there was no significant difference; however, the cholesterol levels were not different between the two groups (Fig.…”

Octacosanol and policosanol prevent high-fat diet-induced obesity and metabolic disorders by activating brown adipose tissue and improving liver metabolism

“…Interscapular BAT (iBAT), iWAT, and eWAT were removed, fixed in 10% buffered formalin, embedded in paraffin, cut into 4 µm thick sections and used for hematoxylin and eosin (H&E) staining and immunohistochemistry as described previously 61 . Immunohistochemical staining for UCP-1 (1:400, ab10983; Abcam, Cambridge, UK) and CD68 (1:400, MCA1957GA; Bio-Rad, Hercules, USA) primary antibodies and detection with secondary antibodies (anti-rabbit IgG, Alexa Fluor 555 conjugate, 1:500, #4413; Cell Signaling Technology Japan, Tokyo, Japan or goat anti-rat IgG, Alexafluor 488 conjugate, 1:500, ab150157; Abcam, Cambridge, UK) was performed as previously described 62 .…”

Notoginsenoside Fe suppresses diet induced obesity and activates paraventricular hypothalamic neurons

“…The adipose tissue participates in the regulation of lipid homeostasis and energy balance by storing energy in the form of TG. 37,38 SREBPs have been established as lipid synthetic transcription factors involved in fatty acids uptake, biosynthesis and metabolism through its downstream gene expression related to de novo lipogenesis, such as ACC, FAS, and fatty acid transport protein CD36. [39][40][41] Recent studies reported that decreased SREBP-1c could inhibit lipogenesis.…”