Carnosic acid against insulin resistance and obesity. Investigating its effects on adipocytes.

Abstract

Adipose tissue plays a crucial role in regulating metabolic homeostasis, and its dysfunction in obesity leads to insulin resistance and type 2 diabetes (T2D). White adipose tissue (WAT) primarily stores energy as lipids while brown adipose tissue (BAT) regulates thermogenesis by dissipating energy in a form of heat. The process of browning involves transdifferention of WAT into brown-like or beige adipocytes, which exhibit the same functional properties as BAT. Browning of WAT is an attractive approach against obesity and insulin resistance. In addition, evidence indicate that activation of the energy sensor AMP-activated protein kinase (AMPK) could counteract insulin resistance. In recent years, chemicals found in plants/herbs have attracted attention for their use as nutraceuticals for preventing and treating insulin resistance and obesity. For example, metformin derived from French Lilac (Syringa vulgaris), has been an established medication in the management of diabetes and hyperglycemia. However, metformin is associated with adverse side effects thereby prompting the search for alternative plant-derived chemicals that may be useful for obesity and diabetes treatment. Rosemary is an evergreen shrub indigenous to the Mediterranean region, which contains various polyphenols. One of the most abundant polyphenols in rosemary is carnosic acid, a compound exhibiting potent antioxidant, antiinflammatory, anticancer, and anti-hyperglycemic properties. Furthermore, based on the limited evidence available, it appears as though carnosic acid may have anti-obesity and antidiabetic potential, but more work needs to be done, and particularly examine its effects on adipocytes. The present studies aim to examine the effects of carnosic acid (CA) on adipocyte browning, on palmitate-induced adipocyte insulin resistance and investigate the role of AMPK. In the first study, it was found that the palmitate-induced insulin resistance was prevented in the presence of CA and the palmitate-induced increase in the activation of mTOR, its downstream target p70S6K, JNK, ERK and Ser307 phosphorylation of IRS-1 were completely blocked while the insulin-stimulated glucose uptake and Akt phosphorylation was restored. In the second study, we show that CA reduced lipid accumulation and increased the expression of browning protein markers (UCP-1, PGC-1α, PRDM16, TFAM) and mitochondrial biogenesis in an AMPK-dependent manner in 3T3- L1 white adipocytes. Conclusion: These studies demonstrate that CA has a pronounced potential in 1) attenuating the palmitate-induced insulin resistance in adipocytes and 2) stimulating browning of white adipocytes in an AMPK-dependent mechanism. Future animal and human studies are required to examine the effects of CA in vivo.