Background The ketogenic diet (KD) is widely recognized for its potential benefits in individuals with type 2 diabetes, but findings from both human and animal studies remain inconsistent. Type 2 diabetes is often comorbid with liver steatosis and atherosclerosis which are characterized by inflammation and dysregulated lipid metabolism. Moreover, whereas KD has shown mixed, sometimes detrimental, effects on circulating cholesterol levels in humans, it is currently unclear the whole-body balance of risk and benefit across hepatic, atherosclerotic, and pancreatic effects. Methods We used lean, diet-induced obese, and diet-induced obese, atherosclerotic (PCSK9 overexpression (OE)) mouse models to assess the impact of an extreme KD on cardiometabolic outcomes. Obese and PCSK9 OE mice received 10 weeks of cholesterol-supplemented HFD before 12 weeks of KD intervention whereas lean mice received KD, chow, or HFD for 12 weeks. Results KD intervention induced weight loss in obese female and PCSK9 OE male mice, but not male, wildtype mice. Across models, KD did not improve glucose tolerance or ex vivo insulin secretion, despite elevated levels of insulinotropic GLP-1 after glucose gavage. Pancreas lipids were similar between diet groups in obese mice, but liver steatosis or inflammation were generally improved in all models on KD. All KD groups had increased hepatic expression of genes for fatty acid oxidation, ketone body production, and ketone utilization. KD-intervened PCSK9 OE mice had lower circulating TNFα and chemokines (CCL2, CCL4, CXCL1, CXCL2) as well as smaller atherosclerotic lesion area relative to mice that continued on the HFD. The PCSK9 OE male mice on KD intervention also had reduced circulating LDL cholesterol but this effect was lost in mice with intact LDL receptor signaling, which also had fasting hypertriglyceridemia in line with HFD continuers. Conclusions This study demonstrates that, in mice, a high cholesterol KD can improve hepatic steatosis particularly when weight loss is achieved, compared to maintaining the western-style HFD. However, no improvements to insulin secretion and glucose tolerance were observed despite elevated post-glucose GLP-1 levels and long-term diminished requirements for insulin.

Background The ketogenic diet (KD) is widely recognized for its potential benefits in individuals with type 2 diabetes, but findings from both human and animal studies remain inconsistent. Type 2 diabetes is often comorbid with liver steatosis and atherosclerosis which are characterized by inflammation and dysregulated lipid metabolism. Moreover, whereas KD has shown mixed, sometimes detrimental, effects on circulating cholesterol levels in humans, it is currently unclear the whole-body balance of risk and benefit across hepatic, atherosclerotic, and pancreatic effects. Methods We used lean, diet-induced obese, and diet-induced obese, atherosclerotic (PCSK9 overexpression (OE)) mouse models to assess the impact of an extreme KD on cardiometabolic outcomes. Obese and PCSK9 OE mice received 10 weeks of cholesterol-supplemented HFD before 12 weeks of KD intervention whereas lean mice received KD, chow, or HFD for 12 weeks. Results KD intervention induced weight loss in obese female and PCSK9 OE male mice, but not male, wildtype mice. Across models, KD did not improve glucose tolerance or ex vivo insulin secretion, despite elevated levels of insulinotropic GLP-1 after glucose gavage. Pancreas lipids were similar between diet groups in obese mice, but liver steatosis or inflammation were generally improved in all models on KD. All KD groups had increased hepatic expression of genes for fatty acid oxidation, ketone body production, and ketone utilization. KD-intervened PCSK9 OE mice had lower circulating TNFα and chemokines (CCL2, CCL4, CXCL1, CXCL2) as well as smaller atherosclerotic lesion area relative to mice that continued on the HFD. The PCSK9 OE male mice on KD intervention also had reduced circulating LDL cholesterol but this effect was lost in mice with intact LDL receptor signaling, which also had fasting hypertriglyceridemia in line with HFD continuers. Conclusions This study demonstrates that, in mice, a high cholesterol KD can improve hepatic steatosis particularly when weight loss is achieved, compared to maintaining the western-style HFD. However, no improvements to insulin secretion and glucose tolerance were observed despite elevated post-glucose GLP-1 levels and long-term diminished requirements for insulin.