Overweight and obesity are risks for many metabolic diseases, posing a serious threat to human health and life. It is now clear that obesity is the result of genome-environment interaction. Obesity is a highly heritable and genetically heterogeneous disorder in humans and rodents. The high-fat diet is an important contributor to weight gain and the development of obesity. Previous studies found that high-fat diet can induce two completely distinct phenotypes in rodents, named diet-induced obesity (DIO) and diet-induced resistance (DR), which has different characteristics in weight, body composition, energy metabolism, feeding preference, etc. However, its internal mechanism is not fully known. Several studies suggested that lipid metabolism in liver, adipose tissue, intestinal tract, and skeletal muscle may contribute to the difference between DIO and DR. Additionally, the changes of gastrointestinal hormone secretion and intestinal inflammation would cause these two phenotypes. Moreover, there was a significant reduction in gut microbiota richness and diversity in DIO mice but not in DR mice, which may play an important role in the development of the obese phenotype. The gut-brain axis made the contributions to the control of food intake and obesity. And the hypothalamic-pituitary-thyroid (HPT) axis function and deiodinases activity might be involved in different propensities to obesity. Difference of NPY/AGRP, POMC/CART and their receptor gene expressions in hypothalamic arcuate nucleus was also the basis of the difference between the two phenotypes. But all these changes of physiology are strongly related to genetic mutations and genotype.