High-Fat Diet Induces Apoptosis of Hypothalamic Neurons

Abstract

Consumption of dietary fats is amongst the most important environmental factors leading to obesity. In rodents, the consumption of fat-rich diets blunts leptin and insulin anorexigenic signaling in the hypothalamus by a mechanism dependent on the in situ activation of inflammation. Since inflammatory signal transduction can lead to the activation of apoptotic signaling pathways, we evaluated the effect of high-fat feeding on the induction of apoptosis of hypothalamic cells. Here, we show that consumption of dietary fats induce apoptosis of neurons and a reduction of synaptic inputs in the arcuate nucleus and lateral hypothalamus. This effect is dependent upon diet composition, and not on caloric intake, since pair-feeding is not sufficient to reduce the expression of apoptotic markers. The presence of an intact TLR4 receptor, protects cells from further apoptotic signals. 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.

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Thus, it seems that long-term obesity results in a resetting of the hypothalamic adipostat, as proposed previously (1,43). Experimental studies have shown that upon prolonged feeding on an HFD, hypothalamic neurons may undergo severe damage that may result in apoptosis (17,44). Interestingly, at least three distinct studies have identified POMC (proopiomelanocortin) neurons as the main targets of inflammation-associated apoptosis (17,44,45).…”

“…Experimental studies have shown that upon prolonged feeding on an HFD, hypothalamic neurons may undergo severe damage that may result in apoptosis (17,44). Interestingly, at least three distinct studies have identified POMC (proopiomelanocortin) neurons as the main targets of inflammation-associated apoptosis (17,44,45). Progressive reduction in hypothalamic POMC neuron population results in an imbalance in POMC/NPY (neuropeptide Y) neurons, which may provide a cellular basis for explaining the resetting of the hypothalamic adipostat.…”

“…Several studies have explored the effects of long-term diet-induced obesity on hypothalamic function (13,14,15,16,17,44,46,47). Dysfunctions of different aspects of the protein homeostasis (proteostasis) machinery have emerged as important mechanisms contributing to hypothalamic neuronal damage.…”

Voluntary exercise improves hypothalamic and metabolic function in obese mice

“…In fact, the orexigenic agouti-related peptide (AgRP)-expressing neuron also resides in the ARC that controls food intake, and ablation of AgRP neuron in adult mice has been shown to result in significantly reduced food intake (Luquet et al 2005). It has also been reported that an HFD induces apoptosis of AgRP neuron (Moraes et al 2009). These results suggest that long-term HFD and exercise training may have broad effects on both orexigenic and anorexigenic neurons in the ARC.…”

High Fat Diet- Induced Neurotoxicity Alters Following vitamin E and C Administration in Hippocampus of Male Rats

“…It has been reported that consumption of a fat-rich diet blunts leptin and insulin orexigenic signaling by a mechanism dependent on in situ activation of inflammation that could induce apoptosis of neurons and a reduction of synaptic inputs in the arcuate nucleus and lateral hypothalamus (31,32). Wang et al showed that apoptotic hepatocytes were significantly greater in livers of rats fed HFD, and these were associated with a higher level of cleaved caspase-3 (33).…”