Prenatal Nicotine Exposure Alters Early Pancreatic Islet and Adipose Tissue Development with Consequences on the Control of Body Weight and Glucose Metabolism Later in Life

Abstract

Despite medical advice, 20-30% of female smokers continue to smoke during pregnancy. Epidemiological studies have associated maternal smoking with increased risk of obesity and type-2 diabetes in the offspring. In the present study, we investigated the impact of prenatal nicotine exposure (3 mg/kg in Sprague Dawley rats via osmotic Alzet minipumps) on the early endocrine pancreas and adipose tissue development in rat pups before weaning. Body weight, fat deposition, food intake and food efficiency, cold tolerance, spontaneous physical activity, glucose utilization, and insulin sensitivity were also examined at adulthood. Prenatal nicotine exposure led to a decrease in endocrine pancreatic islet size and number at 7 d of life (postnatal d 7), which corroborates with a decrease in gene expression of specific transcription factors such as pancreatic and duodenal homeobox 1, Pax-6, Nkx6.1, and of hormones such as insulin and glucagon. The prenatal nicotine exposure also led to an increase in epididymal white adipose tissue weight at weaning (postnatal d 21), and marked hypertrophy of adipocytes, with increased gene expression of proadipogenic transcription factors such as CAAT-enhancer-binding protein-alpha, peroxisome proliferator activated receptor-gamma, and sterol regulatory element binding protein-1C. These early tissue alterations led to significant metabolic consequences, as shown by increased body weight and fat deposition, increased food efficiency on high-fat diet, cold intolerance, reduced physical activity, and glucose intolerance combined with insulin resistance observed at adulthood. These results prove a direct association between fetal nicotine exposure and offspring metabolic syndrome with early signs of dysregulations of adipose tissue and pancreatic development.

Is low birth weight in the causal pathway of the association between maternal smoking in pregnancy and higher BMI in the offspring?

“…We therefore had postulated that fetal nicotine exposure may result in persistent deficits in impulse control and possible decreased control of food consumption (9,11). Surprisingly a poor rather than an increased appetite was observed after fetal nicotine exposure in rats and in 42 year old adults in the 1970 British Cohort Study (51,52). Other mechanisms seem to be likely involved such as a higher food efficiency or lower physical activity.…”

Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice

“…Photographs were then taken using an Axiocam camera (Carl Zeiss, Gottingen, Germany) and the morphometric measurements were performed using the Image J software (Rasband W.S, ImageJ, NIH, Bethesda, MD, USA) as previously reported [26].…”

Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives

“…Epididymal, mesenteric and perirenal fat pad weights are increased in adulthood in Wistar rats perinatally exposed to nicotine (Gao et al 2005). Epididymal fat pad weight is also heavier at weaning in Sprague-Dawley rats exposed to nicotine during their uterine life, mainly due to enhanced differentiation of their adipocytes (Somm et al 2008). Prenatal nicotine exposure also exacerbates post-weaning weight gain and fat deposition caused by high-fat diet consumption (Somm et al 2008).…”

“…Epididymal fat pad weight is also heavier at weaning in Sprague-Dawley rats exposed to nicotine during their uterine life, mainly due to enhanced differentiation of their adipocytes (Somm et al 2008). Prenatal nicotine exposure also exacerbates post-weaning weight gain and fat deposition caused by high-fat diet consumption (Somm et al 2008). Maternal nicotine exposure restricted to the lactating period also leads to early and late metabolic defects.…”

“…Higher levels of HDL-C, leptin, corticosterone and adrenal catecholamine content are observed at PND15, ) and overweight (with increased fat mass and hypertrophy of adipocyte), hyperleptinemia (with impaired hypothalamic leptin signaling), hyperinsulinemia and hypothyroidism are reported in adult rat offspring exposed to nicotine through maternal milk (de Oliveira et al 2010). Different mechanisms could explain the enhanced adipose storage due to early nicotine exposure during the early stage of development such as (1) increased release and transport of fatty acids from maternal adipose tissue to the fetal circulation (Williams and Kanagasabai 1984), (2) a nicotine-mediated stimulatory effect on PPAR-c gene expression in the adipocyte (Somm et al 2008), as previously observed in monocytes (Amoruso Table 2). Interactions between b2 nAChR subunit and nicotine treatment also affects the adipokine expression in both adipose tissues, suggesting that b2 nAChR is involved in control of specific adipokine expression, which is also affected by nicotine Gochberg-Sarver et al (Oliff and Gallardo 1999)]; and (4) decreased cold-induced thermogenesis [in accordance with alterations in adrenergic responsiveness of sympathetic target tissues (Navarro et al 1990) and blunted sympathetic responsiveness leading to hypoactivity of the noradrenergic system (Levin 2005)].…”