Macronutrients represent risk factors for hyperlipidemia or diabetes. Lipid alterations and type 2 diabetes mellitus are global health problems. Overexpression of sterol regulatory element-binding factor ( ) in transgenic animals is linked to elevated cholesterol levels and diabetes development. We investigated the impact of increased locus expression and the effects of control and high-fat, high-sucrose (HFHS) diets on body weight, glucose and lipid metabolisms in transgenic mice ( ). Wild type ( ) and were fed with both diets for 16 weeks. Plasma glucose, insulin and lipids were assessed ( = 25). Immunostainings were performed in liver, pancreas and fat (N = 10). Expression of and in liver was performed by RT-PCR (N = 8). Control diet: showed reduced weight, insulin, total and HDL cholesterol and triglycerides (TG). HFHS diet widened differences in weight, total and HDL cholesterol, insulin and HOMA index but increased TG in . In adipocyte size was lower while HFHS diet produced lower increase, pancreatic β-cell mass was lower with both diets and , and mRNA levels were higher while HFHS diet produced a rise in and levels. complete gene overexpression seems to have beneficial effects on metabolic parameters and to protect against HFHS diet effects.