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Obesity and consequent type-2 diabetes are rising at an epidemic rate in the United States, causing substantial premature mortality and morbidity according to Centers for Disease Control and Prevention (CDC) statistics (Mokdad et al., 2001), approaching smoking as the greatest preventable risk factor for premature death and disability. The proximate causes are relatively straightforward. Overeating and sedentary lifestyle play critical precipitating roles. However, there may be additional causes underlying the skyrocketing obesity and more to the solution of this crisis than just the call to eat less and exercise more.
Control of appetite and expenditure of energy have complex physiological controls. These controls have points of vulnerability to toxic insult that may disrupt weight regulation. The lipophilicity of many toxicants such as polychlorinated biphenyls (PCBs), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and [1,1,1-trichloro-2, 2-bis-(p-chlorophenyl)ethane] (DDT) result in high concentrations of these toxicants in adipocytes. The toxicant doses presented to the adipocytes are higher than for many other cell types. The complex signaling between adipocytes and the rest of the physiology controlling energy expenditure and lipid mobilization may be vulnerable to these higher toxicant doses. Endocrine signaling has been shown to be affected by a variety of environmental toxicants. Disruption of not only sex hormones, such as estrogen, but also hormones regulating metabolism, such as insulin, could be means by which toxicants could influence weight gain and obesity. Finally, neurotoxic actions can provide a means by which toxicants affect appetite and weight regulation. Central neural systems, particularly noradrenergic systems in the brain, have long been known to have critical roles in controlling appetite. Peripheral neural systems also play an important role in weight regulation. Sympathetic autonomic innervation of the adipose tissue provides an important control over fat mobilization. Increased appetite and decreased energy mobilization could be directly influenced by toxic effects on neural control mechanisms.
Neurotoxicity in the central and peripheral nervous system controls over appetite regulation and adipose metabolism may play an important role in the mechanisms of obesity (Levin, 2004b). Fetal nicotinic overload may cause blunting of central and peripheral sympathetic norepinephrine (NE) systems controlling appetite regulation and adipose metabolism and this contributes to overeating and increased weight gain (Levin, 2004a). This central and sympathetic NE blunting may potentiate the obesity caused by a high-fat diet because the normal feedback mechanisms to curb appetite and to decrease lipogenic responses would be blunted by fetal nicotinic overload.
There is empirical support for fetal nicotinic overload potentiating postnatal weight gain. Maternal smoking has been shown in epidemiological studies to be significantly associated with increased risk of obesity in the children. Recent epidemiological studies have provided support for the relationship between prenatal nicotine exposure and obesity in the offspring. The offspring of women who smoked during pregnancy showed significantly greater weight and obesity during childhood and into adulthood (Power and Jefferis, 2002; Toschke et al., 2002; von Kries et al., 2002; Widerøe et al., 2003). The cause-and-effect relationship of maternal smoking and obesity in the offspring can be studied in an experimental rat model. In one of the only studies of prenatal nicotine effects on offspring body weight, Williams and Kanagasabai (1984) found that nicotine administration to pregnant rats significantly increased body fat in the offspring. Our own work supports this and points to blunted sympathetic and central NE response as a cause (Levin and Slotkin, 1998).
We have studied the adverse neurotoxic effects of prenatal nicotine exposure in a rat model (Levin et al., 1993a; 1996). In addition to the persisting alterations in locomotor activity and cognitive function, we found that the offspring of rats exposed to chronic nicotine doses that did not cause alterations in weight gain during gestation or at birth did cause significantly higher weight in the offspring during the juvenile and adolescent periods. Further research is needed to determine the mechanisms of this effect. Our current hypothesis is that it may be related to the underresponsivity of central noradrenergic systems and sympathetic blunting that prenatal nicotine exposure has been shown to cause. Prenatal nicotinic overload could be achieved with other exposures such as the organophosphate pesticides, which could have similar effects.
Adipose tissue has well-defined innervation by the sympathetic nervous system, with sympathetic activation causing lipolysis and mobilization of fats from adipose cells into the bloodstream for use by other parts of the body (Bartness and Bamshad, 1998). With obesity, there is a normal reaction of increased sympathetic tone (Barnes et al., 2003), which would serve to increase lipolysis. If this reactive increase in sympathetic tone was not invoked, lipid would continue to be incorporated in the adipose tissue and obesity would progress.
The sympathetic nervous system develops during the fetal period. Sympathetic development is controlled by a number of genetic and epigenetic factors. Sympathetic connections and reactivity are programmed during prenatal development with fetal sympathetic damage causing long-lasting impairment of sympathetic response, which lasts into adulthood (Alexander and Stevens, 1980). In particular, the impacts of early toxicant exposure of the sympathetic nervous system, which last into adulthood, may represent permanent alterations in sympathetic nervous system function (Young and Morrison, 1998).
Nicotinic cholinergic mechanisms have been shown in our work and that of others (see review Levin and Slotkin, 1998) to be particularly important in the programming of the development of both the sympathetic and central nervous systems, with nicotine, the prototypic nicotinic cholinergic agonist, causing lasting impairments on both sympathetic and central response of NE systems. Central and sympathetic NE systems are critically involved in control of adipose metabolism and appetite (Bartness and Bamshad, 1998). Our hypothesis is that fetal nicotinic overload would result in blunted sympathetic and central NE response, which would cause increased obesity in the offspring.
Nicotinic overload can result either from direct agonists of nicotinic receptors such as with nicotine or neonicotinoid insecticides or indirectly by exposure to acetylcholinesterase inhibitors, which block the catabolic enzyme for acetylcholine, the endogenous ligand for nicotinic receptors. Organophosphate insecticides have pronounced effects on inhibition of acetylcholinesterase. They were designed to have this action in order to cause nicotinic receptor overload in insects, killing them. Because of the widespread use of organophosphate insecticides, there is widespread human exposure, the most common being to chlorpyrifos. There is widespread chlorpyrifos exposure during development (Landrigan et al., 1999; Whyatt et al., 2003). Prenatal and early postnatal chlorpyrifos exposure in a rat model causes neurobehavioral effects, which last well into adulthood (Levin et al., 2001, 2002; Slotkin et al., 2001, 2002; Qiao et al., 2003). There may be persisting effects of fetal chlorpyrifos exposure on weight gain and obesity in adulthood.
The prototypic nicotinic acetylcholine (ACh) agonist nicotine has long been known to have anorectic effects and to result in weight loss or decreased weight gain in both human smokers and experimental animal models (Grunberg et al., 1984; Grunberg, 1986; Klesges and Meyers, 1989; Henningfield et al., 1992). Like others, we have found that chronic nicotine administration (5 mg/kg/day subcutaneous infusion/day) causes a significant decrease in body weight gain in rats relative to controls (Levin et al, 1993b). So why would we posit that prenatal nicotine exposure would underlie obesity in the offspring? The straightforward answer is that fetal nicotinic stimulation has very different effects than nicotinic stimulation in adults. We have shown in a series of studies that fetal nicotinic stimulation causes persistent adverse effects on the central and peripheral nervous systems. Fetal nicotinic overstimulation causes blunting of responsiveness of sympathetic and central NE systems.
FETAL NICOTINE IN RATS
In a test of the persisting neurobehavioral effects of fetal nicotine exposure (Levin et al., 1996), we administered a low nicotine dose of 2 mg/kg/day chronically during gestation. This low dose does not cause a significant decrease in weight gain in pregnant rats during gestation (Fig. 1) (Levin et al., 1996). It also does not significantly affect birth weight. Interestingly, however, this chronic fetal nicotine exposure does cause a significant increase in weight gain after birth (Fig. 2). This is seen even though the offspring were only exposed to bland, relatively low fat lab chow. The effect was not seen later, when feeding was restricted for the neurocognitive testing, which was the focus of the study. Future studies will focus on the weight and feeding effects of fetal nicotine exposure with continued ad libitum feeding and a condition in which a high fat diet is given to the rats.
Fetal nicotinic overload may have effects on weight regulation mediated via blunting of sympathetic and central NE systems, which normally act to increase lipolysis and reduce appetite. The 2 mg/kg/day dose of nicotine administered during gestation to another set of rats caused slight though significant lowering of brain NE levels when only a placebo saline challenge was given (Seidler et al., 1992). Of importance, this fetal nicotine exposure virtually eliminated the increase in NE release normally caused by a challenge dose of nicotine (Seidler et al., 1992), even during the period when NE levels were relatively normal. This blunting of NE responsiveness by fetal nicotinic overload was also seen in further studies.
Peripheral NE responsivity was found to be blunted by fetal nicotinic exposure. The Slotkin laboratory (Navarro et al., 1990) found that NE responsivity of sympathetic innervation of the heart was dramatically reduced (higher doses of agonist needed to have the same physiological effect) even when the NE receptor number was only slightly depressed or not changed by fetal nicotine exposure. This reduced sympathetic responsiveness continued into adulthood.
Central NE responsiveness has also been shown in our previous studies to result from fetal nicotine exposure. Rats exposed to nicotine during fetal development showed under-responsivity to the β-NE antagonist propranolol when tested as adults for working memory function on the eight-arm radial maze (Levin et al., 1993a). Sex-selective effects were seen in a later experiment in which fetal nicotine exposure caused significant blunting of response of female offspring tested as adults for memory on the radial-arm maze when challenge doses α-NE agonist phenylpropanolamine were administered (Levin et al., 1996). There may be possible sex-selective effects of fetal nicotine overload on obesity. This is especially important given the findings by Grunberg et al. (1987) that females are more sensitive to the rapid weight gain after chronic nicotine withdrawal.
FETAL CHLORPHYRIFOS IN RATS
We have published preliminary data that late prenatal chlorpyrifos exposure (5 mg/kg/day on GD 17–20) causes significant increase in weight of the offspring on PND 22 (P < 0.005) of approximately 12% (Levin et al., 2002). Of interest, the same dose of chlorpyrifos given during an earlier prenatal period (5 mg/kg/day on GD 9–12) did not cause a similar effect during the postweaning period (Icenogle et al., 2004).
Fetal toxicant exposure can have lasting effects on a variety of neural, endocrine, and physiological functions. There is interesting evidence (Levin and Slotkin, 1998) that prenatal nicotinic overload blunts sympathetic responsiveness and that this leads to peripheral as well as central underactivity of noradrenergic systems. This may increase appetite and decrease mobilization of fat from adipose tissue. Obesity is a substantial cause of premature death and disability. Toxicant exposure early in life may contribute to the development of obesity later in life. Further research is necessary to determine the extent and mechanisms of toxicant impacts on obesity.