Long-chain polyunsaturated fatty acids and extensively hydrolyzed casein-induced browning in a Ucp-1 reporter mouse model of obesity

Abstract

Browning in adipose tissues, which can be affected by diet, may mitigate the detrimental effects of adiposity and improve longer-term metabolic health. Here, browning-inducing effects of long-chain polyunsaturated fatty acids, e.g., arachidonic acid (ARA)/docosahexaenoic acid (DHA) and extensively hydrolyzed casein (eHC) were investigated in uncoupling protein 1 (Ucp-1) reporter mice. To address the overall functionality, their potential role in supporting a healthy metabolic profile under obesogenic dietary challenges later in life was evaluated. At weaning Ucp1^+/LUC reporter mice were fed a control low fat diet (LFD) with or without ARA + DHA, eHC or eHC + ARA + DHA for 8 weeks until week 12 after which interventions continued for another 12 weeks under a high-fat diet (HFD) challenge. Serology (metabolic responses and inflammation) and in vivo and ex vivo luciferase activity were determined; in the meantime browning-related proteins UCP-1 and the genes peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), PR domain containing 16 (PRDM16) and Ucp-1 were examined. ARA + DHA, eHC or their combination reduced body weight gain and adipose tissue weight compared to the HFD mice. The interventions induced Ucp-1 expression in adipose tissues prior to and during the HFD exposure. Ucp-1 induction was accompanied by higher PGC1a and PRDM16 expression. Glucose tolerance and insulin sensitivity were improved coinciding with lower serum cholesterol, triglycerides, free fatty acids, insulin, leptin, resistin, fibroblast growth factor 21, alanine aminotransferase, aspartate aminotransferase and higher adiponectin than the HFD group. HFD-associated increased systemic (IL-1β and TNF-α) and adipose tissue inflammation (F4/80, IL-1β, TNF-α, IL-6) was reduced. Studies in a Ucp-1 reporter mouse model revealed that early intervention with ARA/DHA and eHC improves metabolic flexibility and attenuates obesity during HFD challenge later in life. Increased browning is suggested as, at least, part of the underlying mechanism.