ABSTRACT: A high-fat diet (HFD) and loss of endogenous estrogens increases the risk for type 2 diabetes (T2D) and insulin resistance. Although exercise is known to prevent and manage insulin resistance, the cellular mechanisms remain largely unknown, especially in the context of a combined HFD and endogenous estrogen loss via ovariectomy (OVX). This study uses female Wistar rats to assess the effect of diet, endogenous estrogens, an exercise on insulin resistance, serum hormones, hepatic AMPK, hepatic regulators of fat metabolism, and expression of signaling molecules of the brain reward pathway. The combination of the HFD/OVX increased the homeostatic model assessment of insulin resistance (HOMA-IR), the glucose-insulin (G-I) index, and the serum adiponectin and leptin values, and exercise decreased these factors. The combination of the HFD/OVX decreased hepatic pAMPK, and exercise restored hepatic pAMPK, an important regulator of fat and glucose metabolism. Furthermore, consumption of the HFD by rats with intact ovaries (and endogenous estrogens) did not result in these drastic changes compared to intact rats fed a standard diet, suggesting that the presence of estrogens provides whole body benefits. Additionally, the HFD decreased the hepatic protein expression of acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS), two proteins involved in de novo lipid synthesis and increased the hepatic protein expression of lipoprotein lipase (LPL), a protein involved in fat storage. Finally, exercise increased mRNA expression of the dopamine D2 receptor and tyrosine hydroxylase in the dopaminergic neuron cell body region of the ventral tegmental area, which is a key component of the brain reward pathway. Overall, this study demonstrates that exercise prevents insulin resistance even when a HFD is combined with OVX, despite hepatic changes in ACC, FAS, and LPL. Graphical abstract Image 1 Highlights • A HFD/OVX increases T2D risk factors, which are decreased with exercise.• A HFD decreases de novo hepatic lipogenesis and increases hepatic fat storage.• Exercise increases D2 and TH mRNA expression in the ventral tegmental area.
