Maternal Consumption of High-Fat Diet Disturbs Hypothalamic Neuronal Function in the Offspring: Implications for the Genesis of Obesity

Abstract

Obesity is a consequence of the loss of the coordinated control of caloric intake and energy expenditure. The homeostasis of this system and, thus, the maintenance of body mass stability depends on the activity of hypothalamic neurons, which are controlled by hormones, nutrients, environmental temperature, and physical activity, providing signals that play pivotal roles in the modulation of hunger, body temperature, motility, and storage of surplus energy (1). Leptin is the most important factor regulating the physiological response to changes in the body energy stores (2). Progressive loss of hypothalamic neuronal response to leptin is a hallmark of obesity, a condition known as hypothalamic resistance to leptin (3). This phenomenon has been characterized at the clinical and molecular levels in experimental models and described, by indirect means, in obese humans (4). As for systemic insulin resistance in type 2 diabetes, hypothalamic resistance to leptin is a consequence of the activation of an inflammatory response in the hypothalamus (5, 6). All of the currently known molecular mechanisms of leptin resistance are activated by inflammatory signals, which target the transduction of the leptin signal by a number of different means. Thus, suppressor of cytokine signaling-3 (SOCS3) can physically block the leptin receptor signal transduction and can also accelerate the proteasome degradation of important downstream targets of this pathway (7); inhibitor of B kinase, C-Jun Nterminal kinase, and protein kinase Ccan catalyze the inhibitory serine phosphorylation of intermediaries of the leptin and insulin signaling systems in the hypothalamus and can also induce the transcription of additional inflammatory genes that boost inflammation in the region (8– 10); and finally, protein tyrosine phosphatase 1B can dephosphorylate and inactivate proteins of the leptin and insulin signaling cascade (11, 12). However, it was only recently that we learned how these inflammatory pathways are triggered. The excessive dietary consumption of saturated fats, one of the most important environmental factors contributing to the global increase of obesity, leads to the activation of signal transduction through Toll-like receptor 4 (TLR4), a receptor of the innate immune system, and the induction of endoplasmic reticulum stress, a cellular mechanism of response to different types of stimuli that can disrupt the physiological protein folding capacity of the endoplasmic reticulum (9, 13). Both these mechanisms can activate inflammation and eventually apoptosis in different cell systems. So far, most studies in this field have focused on adult obesity. However, there are a number of experimental and human studies showing that maternal consumption of high-fat diets during gestation increase the risk for obesity, diabetes, and other components of the metabolic syndrome in the offspring (14, 15). In this issue of Endocrinology, Eva Rother and her colleagues (16) from the University Hospital of Cologne in Germany have evaluated the outcomes of maternal high-fat feeding during gestation and lactation on hypothalamic gene expression in the offspring. According to the experimental approach employed in the study, lean female mice were introduced to a diet containing 35% fat at detection of pregnancy and were maintained on this diet throughout gestation and lactation until