Whey Peptides Stimulate Differentiation and Lipid Metabolism in Adipocytes and Ameliorate Lipotoxicity-Induced Insulin Resistance in Muscle Cells

Abstract

Deregulation of lipid metabolism and insulin function in muscle and adipose tissue are hallmarks of systemic insulin resistance, which can progress to type 2 diabetes. While previous studies suggested that milk proteins influence systemic glucose homeostasis and insulin function, it remains unclear whether bioactive peptides generated from whey alter lipid metabolism and its accumulation in muscle and adipose tissue. Therefore, we incubated murine 3T3-L1 preadipocytes and C2C12 myotubes with a whey peptide mixture produced through pepsin-pancreatin digestion, mimicking peptides generated in the gut from whey protein hydrolysis, and examined its effect on indicators of lipid metabolism and insulin sensitivity. Whey peptides, particularly those derived from bovine serum albumin (BSA), promoted 3T3-L1 adipocyte differentiation and triacylglycerol (TG) accumulation in accordance with peroxisome proliferator-activated receptor γ (PPARγ) upregulation. Whey/BSA peptides also increased lipolysis and mitochondrial fat oxidation in adipocytes, which was associated with the upregulation of peroxisome proliferator-activated receptor δ (PPARδ). In C2C12 myotubes, whey but not BSA peptides ameliorated palmitate-induced insulin resistance, which was associated with reduced inflammation and diacylglycerol accumulation, and increased sequestration of fatty acids in the TG pool. Taken together, our study suggests that whey peptides generated via pepsin-pancreatin digestion profoundly alter lipid metabolism and accumulation in adipocytes and skeletal myotubes.

Bioconversion Products of Whey by Lactic Acid Bacteria Exert Anti-Adipogenic Effect

“…Enriched whey protein fractions inhibit adipogenesis of 3T3-L1 ( Rajic et al, 2010 ). More recently, D’Souza et al (2020) demonstrated that whey protein hydrolyzed by pepsin and pancreatin enhances 3T3-L1 adipocyte differentiation and triacylglycerol accumulation. However, it has not yet been reported that bioconversion of whey exerts an anti-adipogenic effect.…”

Branched‐chain amino acids at supraphysiological but not physiological levels reduce myotube insulin sensitivity

“…Furthermore, the addition of leucine to evogliptin treatment in high‐fat‐fed mice has also been shown to improve glucose tolerance (an effect not observed in evogliptin‐only group) 36 . In vitro, C2C12 myotubes treated with hydrolysed whey protein isolate showed restoration of palmitate‐suppression of pAkt signaling and GLUT4 expression 37 . Moreover, treatment with an isoleucine‐leucine dipeptide previously improved glucose uptake in L6 myotubes 38 .…”

Whey Protein Supplementation Effects on Body Composition, Performance, and Blood Biomarkers During Army Initial Entry Training

“…Animal and cell culture models suggest WP may promote fat metabolism by influencing both adipose and muscle ( 43 , 44 ). WP has been shown to impact adipose tissue by upregulating signaling pathways associated with the breakdown of triglycerides into FFA ( 43 , 44 ), fat oxidation ( 45 ), thermogenesis ( 43 ), and antagonists to fatty acid synthesis ( 44 ). Conversely, in myotubes, WP has been shown to upregulate signaling pathways related to free fatty acid transport to mitochondria ( 43 ) and mitochondrial ability to oxidize free fatty acids ( 44 ).…”