Abstract
Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristics in offspring. Female Sprague-Dawley rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation, and their offspring were weaned to normal or HFD. The offspring were randomized to Exd-4 or placebo from weaning and their kidneys harvested at Week 9. We found that the kidneys of offspring from obese mothers, regardless of postnatal diet, had significantly increased markers of inflammation, oxidative stress and fibrosis. Exd-4 ameliorated the negative renal effects of maternal obesity and in particular, reduced renal inflammation, oxidative stress and fibrosis. In conclusion, maternal obesity has persisting effects on renal structure in the offspring. GLP-1 analogues are potentially useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring.
Highlights
The metabolic consequences of obesity have been well described and include type 2 diabetes, insulin resistance, non-alcoholic fatty liver disease, dyslipidaemia and hypertension
We have previously shown that offspring of obese rat dams display increased fat mass, elevated blood triglyceride levels and glucose intolerance compared with those from lean rats, which is further exaggerated by consuming a high fat diet (HFD) after weaning[16]
At 15- and 30- minute during intraperitoneal glucose tolerance test (IPGTT), there was a significant rise in blood glucose levels in the HFD-fed offspring group (HH), compared with the control group (CC) (p < 0.05 at both time-points, Fig. 1E)
Summary
The metabolic consequences of obesity have been well described and include type 2 diabetes, insulin resistance, non-alcoholic fatty liver disease, dyslipidaemia and hypertension. A recent study showed that the risk of CKD was over 2.5 times higher in obese individuals compared with normal-weight individuals after adjusting for confounding factors including diabetes and hypertension[4]. Maternal obesity in pregnancy is associated with lifelong metabolic consequences in the offspring, including obesity, dyslipidemia, insulin resistance and type 2 diabetes[10,11]. Maternal obesity and its effects on offspring have raised considerable public interest, especially considering that adult progeny of obese mothers have a 22% increased risk of cardiovascular disease, stroke, and all-cause mortality independent of their own weight[12]. The current study utilized a rodent model to investigate whether maternal obesity has detrimental renal effects on the offspring; in particular promoting CKD by altering glucose and lipid metabolism, oxidative stress, inflammation, and fibrosis within the kidney. We hypothesized that the treatment of offspring with Exd-4 would reduce renal inflammation, oxidative stress and fibrotic changes induced by maternal obesity
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