Increased consumption of dietary fats is regarded as one of the most important environmental factors predisposing to obesity in modern societies 
. The ability of dietary fats to promote body mass gain is not exclusively due to its energetic value since prolonged caloric pair-feeding retains most of the obesogenic potential of different high-fat diets 
. Therefore, elucidating the complete mechanisms involved in high fat diet-induced obesity is of major importance to understand the pathophysiology of most cases of human obesity.
Considerable advance in this field was provided by the recent demonstration of the activation of an inflammatory response in the hypothalamus of animal models of diet-induced obesity 
. According to these studies, the consumption of a high-fat diet activates the expression or the activity of inflammatory responsive proteins such as SOCS3, IKK, JNK and PTP1B which impair leptin and insulin signaling in the hypothalamus, thus, disrupting the main satietogenic and adipostatic routes that maintain a stable body mass. The importance of such a mechanism is further illustrated by the fact that both genetic and pharmacological inhibition of inflammatory signaling in the hypothalamus can reverse or prevent the installation of diet-induced obesity 
A rather frequent outcome of the activation of inflammatory signal transduction is the induction of pro-apoptotic signaling 
. Cytokines such as TNF-α and IL-1β, which are highly expressed in the hypothalami of rodents fed on a high-fat diet 
, can induce apoptosis of different cell types 
. As an example of this, in a recent study we observed that, upon icv treatment, TNF-α activates apoptotic signaling in the hypothalamus 
. Therefore, in the first part of the study, we explored the pro-apoptotic potential of the high-fat diet evaluating the expressions of 84 apoptosis related genes by real-time PCR array. First, we showed that the diet protocol herein employed was capable of inducing the activation of markers of inflammation and resistance to leptin and insulin anorexigenic activity in the hypothalamus, as previously demonstrated in other studies 
The effect of the diet upon the expressions of pro- and anti-apoptotic genes was remarkable. The modulation of 57% of the targets, including proteins involved in both pro- and anti-apoptotic activity, suggests that the fat-rich diet indeed has a damaging effect. As observed in other experimental settings, we suspect that the activation of some anti-apoptotic proteins provides a transient protection against the harmful effects of the diet 
. However, as shown by distinct methods, ranging from TUNEL to transmission electron microscopy, in spite of the presence of anti-apoptotic activity, apoptosis was significantly increased in the hypothalamus of the HF rats. This was an anatomical- and cell-specific phenomenon since it was detected predominantly in the hypothalamus and affected mostly neurons.
Interestingly, in Wistar rats, which develop a certain degree of obesity and do not become diabetic, the diet produced a similar reduction in the expressions of orexigenic and anorexigenic neurotransmitters, suggesting that apoptosis was evenly distributed among neuronal sub-populations. However, in Swiss mice, which are genetically related to the diabetes prone AKR mouse 
and, likewise, display an outstanding propensity to obesity and diabetes 
, the level of POMC was significantly reduced as compared to control, suggesting that this subpopulation of neurons was predominantly targeted. Although we have no current mechanistic explanation for this phenomenon, we suspect that, by targeting different subpopulations of neurons, diet-induced hypothalamic apoptosis leads to an imbalance in orexigenic vs.
anorexigenic neurons in Swiss mice, but not in Wistar rats, therefore favoring body mass gain only in the mice. Two recent studies have provided strong evidence to suggest that changes in the numbers of certain types of hypothalamic neurons may have an impact on the control of body adiposity. First, Ryu and colleagues 
reported that arcuate nucleus neurodegeneration caused by the depletion of Ubb, a protein involved in the production of ubiquitin, can affect energy homeostasis and lead to obesity. In addition, Kokoeva and coworkers 
showed that hypothalamic neurogenesis induced by CNTF explains much of the sustained weight-reducing effect of this protein, a phenomenon that can be avoided by the use of an anti-mitotic agent. Therefore, we believe that, depending on genetic background and on different environmental factors, changes in neurogenesis and survival rates of hypothalamic neurons can have an impact on body adiposity.
Similarly to the effect of high-fat diets on body mass gain, here we show that activating apoptotic proteins in the hypothalamus is a property of the diet composition and not of the caloric intake. Caloric pair-feeding retained most of the pro-apoptotic activity of ad libitum feeding.
Recent data from ours and other groups have shown that inflammatory signaling through TLR4 plays an important role in diet-induced insulin resistance and diabetes 
. TLRs are highly-conserved members of the interleukin-1 receptor superfamily that respond to microbial signature motifs, leading to the activation of innate immune responses 
. Some members of the TLR family are known to recognize lipid-containing motifs, such as lipopolysaccharides (LPS), which are ligands for TLR4. Whenever active, signal transduction through TLR4 leads to the coordinated induction of cytokine and other immune related genes expression 
When we tested the hypothesis that TLR4 could mediate some of the pro-apoptotic effects of the HF diet, we obtained data that, surprisingly suggested that the presence of this receptor may be protective, rather than harmful, for cells.
Although at first sight this data may seem unexpected, recent studies have provided evidence for a protective role for TLRs in the central nervous system 
. In many conditions, TLRs are known to mediate detrimental signals, favoring the progression of inflammatory diseases of the brain. However, an appropriately-controlled TLR activity is also important for preserving the structure and function of neural tissues exposed to harmful conditions 
. In two previous studies the loss of TLR4 function protected against inflammation and insulin or leptin resistance 
, however, on a long run, at least one study reported that in the absence of TLR4 signaling, body adiposity would increase upon high-fat diet consumption 
. Thus, it is likely that, in diet-induced inflammation of the hypothalamus, TLR4 exerts a dual function, on one side activating pro-inflammatory pathways that play a central role in the development of resistance to leptin and insulin, and on the other side restraining further damage by controlling the apoptotic activity.
As an outcome of the present study, it will be important to investigate the proposed dual role for TLR4 in the hypothalamus, participating in the balance between inflammation and cell survival. In addition, as recent studies have shown that insulin and leptin resistance in extra-hypothalamic brain regions may relate to neurological disorders, such as Alzheimer's disease and depression 
, it will be exiting to evaluate the participation of TLRs and high-fat feeding in these contexts.