Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice

Abstract

The transcription factor carbohydrate response element-binding protein (ChREBP) mediates insulin-independent, glucose-stimulated gene expression of multiple liver enzymes responsible for converting excess carbohydrate to fatty acids for long-term storage. To investigate ChREBP's role in the development of obesity and obesity-associated metabolic dysregulation, ChREBP-deficient mice were intercrossed with ob/ob mice. As a result of deficient leptin expression, ob/ob mice overeat, become obese and resistant to insulin, and display marked elevations in hepatic lipogenesis, gluconeogenesis, and plasma glucose and triglycerides. mRNA expression of all hepatic lipogenic enzymes was significantly lower in ob/ob-ChREBP-/- than in ob/ob mice, resulting in decreased hepatic fatty acid synthesis and normalization of plasma free fatty acid and triglyceride levels. Overall weight gain in addition to adiposity was reduced in the doubly deficient mice. The former was largely attributable to decreased food intake and may result from decreased hypothalamic expression of the appetite-stimulating neuropeptide agouti-related protein. mRNA expression and activity of gluconeogenic enzymes also was lower in the doubly deficient mice, contributing to significantly lower blood glucose levels. The results of this study suggest that inactivation of ChREBP expression not only reduces fat synthesis and obesity in ob/ob mice but also results in improved glucose tolerance and appetite control.

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

“…Because ChREBP is induced by dietary carbohydrate, the generally held explanation for ChREBP function is that it represents a mechanism for efficient conversion of dietary carbohydrate to fat as a 'thrifty gene' (8)(9)(10)(11) . The decrease in DNL (37)(38)(39) and in steatosis (38,39) in ChREBP knock-down models (37) is consistent with such a hypothesis but it does not exclude the alternative explanation (25) that the role of DNL is regulatory for fuel selection because it is not a quantitative route of carbohydrate disposal (25,28) . ChREBP binds to the promoter of its target genes in complex with Max-like protein X (Mlx), a member of the Myc/Max superfamily of transcription factors (9,40) .…”

Metabolite Regulation of Nucleo-cytosolic Trafficking of Carbohydrate Response Element-binding Protein (ChREBP)

“…Male rats 6 -10 weeks of age were housed in temperature-controlled facilities with 12-h light/dark cycles and maintained on standard rodent chow ("NIH") (HarlanTeklad Mouse/Rat Diet 7002; Harlan-Teklad Premier Laboratory Diets). The high sucrose ("HS") and high fat ("HF") diets were described as before (17).…”

Role of glucose-6-phosphate and xylulose-5-phosphate in the regulation of glucose-stimulated gene expression in the pancreatic β cell line, INS-1E

“…These studies reported that G6P produced by glucokinase, but not X5P, is essential for both ChREBP nuclear translocation and transcriptional activity in response to glucose in liver cells [15]. This is a feasible idea because: (1) in ChREBP knockout mice, the hepatic G6P and glycogen content are increased [4,5], and (2) ChREBP can regulate G6P concentration through the induction of glucose-6-phosphatase (G6pase) and glucose-6-phophate dehydrogenase (G6pdh) gene expression [4,5]. However, there are several problems with these pGL3-3×TXNIP ChoRE promoter was constructed by cloning a fragment of 3×TXNIP ChoRE (ctgtgCACGAGggctgCACGAGcctccctgtgCACGAGggctgCACGAGcctccctgtgCACGAGggctgCACGAGcctcc) upstream of the SV40 promoter in the pGL3 vector.…”