Ala supplementation led to more pronounced metabolic improvements compared to Arg, possibly due to suppression of lipogenesis through activation of the AMPK/ACC pathway.

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Increased adiposity in perivascular adipose tissue (PVAT) has been related to vascular dysfunction. High-fat (HF) diet-induced obesity models are often used to analyze the translational impact of obesity, but differences in sex and Western diet type complicate comparisons between studies. The role of PVAT was investigated in small mesenteric arteries (SMAs) of male and female mice fed a HF or a HF plus high-sucrose (HF + HS) diet for 3 or 5 months and compared them to age/sex-matched mice fed a chow diet. Vascular responses of SMAs without (PVAT-) or with PVAT (PVAT+) were evaluated. HF and HF + HS diets increased body weight, adiposity, and fasting glucose and insulin levels without affecting blood pressure and circulating adiponectin levels in both sexes. HF or HF + HS diet impaired PVAT anticontractile effects in SMAs from females but not males. PVAT-mediated endothelial dysfunction in SMAs from female mice after 3 months of a HF + HS diet, whereas in males, this effect was observed only after 5 months of HF + HS diet. However, PVAT did not impact acetylcholine-induced relaxation in SMAs from both sexes fed HF diet. The findings suggest that the addition of sucrose to a HF diet accelerates PVAT dysfunction in both sexes. PVAT dysfunction in response to both diets was observed early in females compared to age-matched males suggesting a susceptibility of the female sex to PVAT-mediated vascular complications in the setting of obesity. The data illustrate the importance of the duration and composition of obesogenic diets for investigating sex-specific treatments and pharmacological targets for obesity-induced vascular complications.

Obesity predisposes to glucose intolerance and type 2 diabetes (T2D). This disease is often characterized by insulin resistance, changes in insulin clearance, and β-cell dysfunction. However, studies indicate that, for T2D development, disruptions in glucagon physiology also occur. Herein, we investigated the involvement of glucagon in impaired glycemia control in monosodium glutamate (MSG)-obese mice. Male Swiss mice were subcutaneously injected daily, during the first 5 days after birth, with MSG (4 mg/g body weight [BW]) or saline (1.25 mg/g BW). At 90 days of age, MSG-obese mice were hyperglycemic, hyperinsulinemic, and hyperglucagonemic and had lost the capacity to increase their insulin/glucagon ratio when transitioning from the fasting to fed state, exacerbating hepatic glucose output. Furthermore, hepatic protein expressions of phosphorylated (p)-protein kinase A (PKA) and cAMP response element-binding protein (pCREB), and of phosphoenolpyruvate carboxykinase (PEPCK) enzyme were higher in fed MSG, before and after glucagon stimulation. Increased pPKA and phosphorylated hormone-sensitive lipase content were also observed in white fat of MSG. MSG islets hypersecreted glucagon in response to 11.1 and 0.5 mmol/L glucose, a phenomenon that persisted in the presence of insulin. Additionally, MSG α cells were hypertrophic displaying increased α-cell mass and immunoreactivity to phosphorylated mammalian target of rapamycin (pmTOR) protein. Therefore, severe glucose intolerance in MSG-obese mice was associated with increased hepatic glucose output, in association with hyperglucagonemia, caused by the refractory actions of glucose and insulin in α cells and via an effect that may be due to enhanced mTOR activation.