Research Article: A casein hydrolysate based formulation attenuates obesity and associated non-alcoholic fatty liver disease and atherosclerosis in LDLr-/-.Leiden mice

Date Published: July 5, 2017

Publisher: Public Library of Science

Author(s): Marieke H. Schoemaker, Robert Kleemann, Martine C. Morrison, Joanne Verheij, Kanita Salic, Eric A. F. van Tol, Teake Kooistra, Peter Y. Wielinga, Patricia Aspichueta.


Obesity frequently associates with the development of non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. Chronic inflammation in white adipose tissue (WAT) seems to be an important driver of these manifestations.

This study investigated a combination of an extensively hydrolyzed casein (eHC), docosahexaenoic acid (DHA), arachidonic acid (ARA), and Lactobacillus Rhamnosus GG (LGG) (together referred to as nutritional ingredients, NI) on the development of obesity, metabolic risk factors, WAT inflammation, NAFLD and atherosclerosis in high-fat diet-fed LDLr-/-.Leiden mice, a model that mimics disease development in humans.

LDLr-/-.Leiden male mice (n = 15/group) received a high-fat diet (HFD, 45 Kcal%) for 21 weeks with or without the NI (23.7% eHC, 0.083% DHA, 0.166% ARA; all w/w and 1×109 CFU LGG gavage 3 times/week). HFD and HFD+NI diets were isocaloric. A low fat diet (LFD, 10 Kcal%) was used for reference. Body weight, food intake and metabolic risk factors were assessed over time. At week 21, tissues were analyzed for WAT inflammation (crown-like structures), NAFLD and atherosclerosis. Effects of the individual NI components were explored in a follow-up experiment (n = 7/group).

When compared to HFD control, treatment with the NI strongly reduced body weight to levels of the LFD group, and significantly lowered (P<0.01) plasma insulin, cholesterol, triglycerides, leptin and serum amyloid A (P<0.01). NI also reduced WAT mass and inflammation. Strikingly, NI treatment significantly reduced macrovesicular steatosis, lobular inflammation and liver collagen (P<0.05), and attenuated atherosclerosis development (P<0.01). Of the individual components, the effects of eHC were most pronounced but could not explain the entire effects of the NI formulation. A combination of eHC, ARA, DHA and LGG attenuates obesity and associated cardiometabolic diseases (NAFLD, atherosclerosis) in LDLr-/-.Leiden mice. The observed reduction of inflammation in adipose tissue and in the liver provides a rationale for these comprehensive health effects.

Partial Text

The prevalence of overweight and obesity has risen dramatically in the past decades worldwide.[1] Obesity is a hallmark of the metabolic syndrome which represents a major global health problem that frequently associates with the development of non-alcohol fatty liver disease (NAFLD), and cardiovascular disease (CVD) as complications.

In this study, we investigated the combined effect of specific nutritional ingredients (NI) with beneficial health effects, i.e. an extensively hydrolyzed casein, the LC-PUFAs DHA and ARA and the probiotic LGG, on the development of obesity and its comorbidities NAFLD and atherosclerosis. The study was performed in LDLr-/-.Leiden mice which develop obesity and dyslipidemia and associated NAFLD and atherosclerosis when treated with HFD. In this translational model, the applied concentration of fat is also reached in human diets [33], and NAFLD and atherosclerosis were scored using human-based grading systems.[27, 34, 35] The tested combination of NI mitigated HFD-induced obesity and the development of associated complications, NAFLD and atherosclerosis.

In conclusion, our data provide evidence that a combination of specific NI (extensively hydrolyzed casein, LC-PUFAs ARA and DHA, LGG) can reduce obesity and metabolic diet-induced inflammation at organ level (adipose tissue, liver) with pronounced attenuating effects on NAFLD and atherosclerosis. These results advocate research on dietary approaches for the management of obesity and its comorbidities and warrants further studies in humans.




0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments