Effects of Intermittent Feeding in the Appetite Control Center of the Brain (Hypothalamus)
I have written extensively regarding the health benefits associated with time of eating and intermittent fasting:
MORE EVIDENCE THAT MEAL TIMING CORRELATES WITH OBESITY
A new study published in the journal, Nutrition, examines the effects of intermittent fasting (IFR: intermittent food restriction) on the expression of genes in the hypothalamus whose encoded proteins are critical to the control of energy homeostasis and feeding behavior. The results suggest that long term intermittent fasting is associated with increased expression of hypothalamic genes whose encoded proteins are critically involved in energy imbalance suggesting that caution should be exercised when adopting an intermittent fasting type diet. Granted these studies were carried out in laboratory animals, nonetheless there is ample evidence of the high degree of similarity in the control of feeding behaviors elicited by the hypothalamus in mammals.
The details of the role of the hypothalamus in the control of feeding behaviors are covered in the Gut-Brain Interrelationships and the Control of Feeding Behavior page of my website. However, it will be useful to briefly discuss here, the role of the hypothalamus, and the neuropeptide derived from this brain region, in the control of feeding behavior.
The hypothalamus is located below the thalamus and just above the brain stem and is composed of several domains (nuclei) that perform a variety of functions. The hypothalamus forms the ventral portion of the region of the brain called the diencephalon. The various nuclei of the hypothalamus constitute the functional domains of the various hypothalamic areas. The primary nuclei of the hypothalamus that are involved in feeding behaviors and satiety (the sensation of being full) include the arcuate nucleus of the hypothalamus (ARC, also abbreviated ARH), the dorsomedial hypothalamic nucleus (DMH or DMN), and the ventromedial hypothalamic nucleus (VMH or VMN). All three of these nuclei are located in the tuberal medial area of the hypothalamus. The ARC is involved in the control of feeding behavior as well as in the secretion of various pituitary releasing hormones. The DMH is involved in stimulating gastrointestinal activity. The VMH is involved in neural signals that elicit the sensations of satiety.
The ARC is composed of a variety of functional neurons with the orexigenic (hunger inducing) neurons expressing neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and the anorexigenic (appetite suppressing) neurons expressing pro-opiomelanocortin, POMC (yielding the neurotransmitter α-MSH) and cocaine and amphetamine-regulated transcript (CART). These ARC neurons are referred to as first order neurons and they release their neurotransmitters to act on second order orexigenic neurons (containing either melanin concentrating hormone, MCH or orexin) or anorexigenic neurons (expressing corticotropin releasing hormone, CRH) to alter feed intake. In addition, satiety signals from the liver and gastrointestinal tract signal through the vagus nerve to the nucleus of the solitary tract (NTS, for the Latin term nucleus tractus solitarii) to cause meal termination, and in combination with the hypothalamus, integrate the various signals to determine the feeding response. The activities of these neuronal pathways are also influenced by numerous factors such as nutrients, fasting, and disease to modify appetite and hence to exert impacts on growth and reproduction.
A common pathophysiological association in obesity is chronic inflammation which, in and of itself, significantly contributes to cardiovascular disease. Dietary excess of refined sugars and saturated fatty acids is known to trigger acute inflammatory responses throughout the body. Within the brain this acute inflammation results in impaired energy balance which, in the long term, is a contributing factor in overweight and obese states.
Within the hypothalamus proper signaling by insulin and leptin (an adipose tissue protein) is required normal feeding behavior responses within the ARC to occur. Inflammation-associated proteins such as c-Jun N-terminal kinase (JNK) and the suppressor of cytokine signaling 3 (SOCS3) have the ability to inhibit both the insulin- and leptin-mediated hypothalamic regulatory pathways. Additional protein related to inflammatory responses, that are involved in hypothalamic energy balance, are toll-like receptor 4 (TLR-4), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and inhibitor of NFκB kinase subunit beta (IKKβ). Activation of TLR-4 leads to downstream activation of IKKβ and NFκB which in turn activate expression of numerous inflammatory cytokine encoding genes. This in turn activates JNK which results in perpetuation of the pro-inflammatory state.
Numerous studies in humans have demonstrated that intermittent food restriction (IFR) can exert certain positive effects, such as reducing body mass, enhancing insulin sensitivity, and lowering cardiovascular risk. The problem for humans with this type of dieting is adherence which is limiting for the analysis of the long-term effects of IFR given that studies in animals have indicated an association between long-term IFR and energy imbalance.
The goal of this study was to examine the effects of long-term IFR on the expression of hypothalamic genes whose encoded This study was conducted by dividing animals into four groups. The standard control group (ST-C) animals were fed with an ad libitum standard diet. The diet-induced obesity control group (DIO-C) animals were fed a diet-induced obesity diet in the first and last 15 days of the study and a standard diet between the 16th and 45th day. The standard restricted group (ST-R) animals were fed with a standard diet in the first and last 15 days of the study followed by intermittent food restriction (IFR) at 50% of the ST-C diet between the 16th and 45th day. The diet-induced obesity restricted group (DIO-R) animals were fed with a DIO diet in the first and last 15 days of the study and subjected to IFR under the same conditions as the ST-R group. Analysis of hypothalamic gene expression was undertaken at 105 days, the equivalent of approximately 11 years to humans.
The critical result from the work presented in this paper is that intermittent food restriction (IFR), whether or not it was associated with a diet that was high-fat, high-sugar, or obesogenic
diet (DIO), was capable of altering the expression of key genes involved in energy regulation imbalance in the hypothalamus. This study found that hypothalamic expression of both IKKβ and NFκB was higher in both IFR groups independent of the changes to TLR-4 expression. The increase in IKKβ and NFκB expression indicates that IFR is associated with increased inflammation. Another inflammation associated gene, chemokine ligand 5 (CCL5), which is also known as regulated on activation, normal T cell expressed and secreted (RANTES), in the DIO-R group.
TAKE AWAY: Given the findings from this study, although carried out in animals, it is justifiable to exercise caution with the use of long-term intermittent food restriction (IFR) given the potential for hypothalamic inflammation and energy imbalance.
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