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  1. An excerpt from the book:


                 The medical consequenses of High-(Fat)/protein, Low-Carbohydrate Diets.

                                    by Dr. Magda Robinson,  BM

Saturted fat and arachidonic acid.  p. 101 & 102

A high saturated fat diet is known to increase cancer risk.  There several studies which illustrate the tumour promoting effects of a high saturated fat diet in breast cancer (Khalid et al. 2009), non-Hodgkins lymphoma (Zhang et al. 1999), and in colorectal carcinoma (van Suan et al. 2009).  The former rodent study reported a tumour promoting effect of a low-carbohydrate (35%), high-fat (45%) diet (mostly in the form of lard) compared with a high-caarbohydrate (70%), low-fat (10%) fat diet.  (The protein content was the same at 20%).  Note that in comparison, classic (high protein low carbohydrate (HPLC) diets have even higher levels of fat and saturated fat: the Atkins diet is 60% fat and 26% saturated fat, and the Protein Power diet is 53% fat and 19% saturated fat (Eades 2009).  The implications for cancer promotion are alarming.

The Zhang et al. study demonstrated that the risk of non-Hodgkns lymphoma was more that twice as likely in people who ate beef, pork or lamb at least once a day compared with less than once a week.  The result of consumption of trans fats was similar, more than doubling the risk of nonn-Hodgkins lymphoma between the highest and lowest quantiles. 

The van Suan et al. study examined the effects o feeding a reduced carbohydrte (42.7%), high-fat (42%) diet to mice.  The fat was mostly saturated, deriving all from milk fat.  The lvers of these mice were compared with mice fed standard chow, i.e. a normal carbohydrate (58%) and low-fat (13.5%) diet.  The high-fat diet group rapidly developed hapatic steatosis and livers of treble the weight of the low-fat diet.  Histology after 14 months on the diet revealed primary dysplastic nodules in 100% of the mice, compared with 0% of the mice on the standard low-fat diet.  Furthermore, when colonic cancer cells were injected into the spleen, the number of metastatic tumours in the liver in teh high-fat diet group was 4.8 times the number found in the loow-fat diet group.  Thus a high saturated fat diet caused a microenvironment in the liver conducive to the development of both primary and secondary tumours.

There are several different potential mechanisms for the link between dietary fat and carcinogenesis.  Arachidonic acid is the precursor to several different pro-inflamatory molecules which directly activate nuclear factor kappa beta (NF-kB).  This gene transcription factor drives the inflamatoryu responses of the immune system and is strongly linked with a raised cancer risk.  Saturated high-fat diets indirectly activate NF-kB and contribute to cancer risk. Confirming these mechanisms, the WCRF/AICR updated reort on colorectal cancer states, "Saturated fatty acids can induce expression of inflammatory mediators and stimulate increased insulin production" (WCRF 2011). 

WCRFI: World Cancer Research Fund International.


2. The association of high saturated fat diet and NF-kB (promoting cancer) is shown in the following excerpt:

Journal of Nutritional Biochemistry 42:2017;1-6.


Fatty-acid-mediated hypothalamic inflammation and epigenetic programming

Helena C. Cesar and Luciana Pellegrini Pisani


2.1. The association between fatty acids and hypothalamic inflammation

In 2005, De Souza et al. [11] were the first to identify hypothalamic inflammation associated with insulin resistance in rats after 16 weeks of a high-fat diet (39% of kcal from lard). Further experiments confirmed these findings and discovered that, unlike peripheral inflammation that occurs after adipocyte hypertrophy, central inflammation induced by a high-fat diet occurs only after 24 h and before weight gain is significant [13]. Therefore, the effects of a high-fat diet seem to initiate in the CNS and affect other tissues only after prolonged consumption of a high-fat diet. Thaler et al. (2012) [13] fed adult rats with a high-fat diet (54% of kcal from lard) for 20 weeks, and they saw increased food intake and weight gain in the treatment group compared to controls. Concomitantly, they found in the treated group an increased expression of proinflammatory markers in the hypothalamus after only 4 weeks on a high-fat diet, which was not seen in the adipose tissue and liver of the animals. Interestingly, these researchers also found that increases in the expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, suppressor of cytokine signaling 3 (Socs3), I-kappa-B-kinase beta and I-kappa-B kinase epsilon caused a proportionate increase in food intake during the first days. This shows a possible link between hypothalamic inflammation and enhanced energy intake even before the onset of obesity or increased accumulation of adipose tissue.

The mechanisms involved in the hypothalamic inflammation are not completely known, but recent evidence points to gliosis and direct neural injury caused by high-fat diet (high in saturated fats) [[2][3][13]]. Gliosis is a response of the CNS to neural injury, and it is characterized by recruitment, activation and proliferation of neural-immune cells [14]. Thaler et al. (2012) [13] found increased accumulation, activation and cell size of microglia in the ARC from mice and rats fed high-fat diet, and it positively correlated with fat mass size. Likewise, the same pattern was observed in humans; a retrospective cohort of 34 people free from abnormalities was subjected to magnetic resonance imaging. This identified the presence of gliosis in the MBH, which correlated with BMI. The molecular mechanisms participating in the activation of hypothalamic inflammation are the activation of Toll-like receptor 4 (TLR-4), induction of ER stress and activation of IKKβ [15].

Like macrophages in the periphery, microglia abundantly express TLR-4, a signal-transducing receptor that responds to saturated fats through IKKβ/NFκB pathway to release proinflammatory cytokines (such as IL-6 and TNF-α) [[16][17]]. TLR-4 is overexpressed in obesity, and its inhibition by intracerebroventricular (ICV) injections, with immunoneutralizing antibodies against TLR-4, brings about the recovery in leptin and insulin signaling and improvement in liver metabolism [18]. Moreover, dietary fats can easily flux into the hypothalamus, and microglia have access to these fats rapidly. Experiments on mice fed saturated fats from milk fat (C16:0 palmitic and C18:0 stearic fatty acids) resulted in increased accumulation of saturated fats in the hypothalamus, accumulation and activation of microglia in the MBH and increased TNF-α release (Fig. 2) [2]. In addition, high-fat diet and saturated fats up-regulate the expression of heat-shock protein 72, a protein involved in the neuronal stress response [[2][13]]. However, it is still unclear whether the neuronal stress is a result of microglia response to saturated fats or a direct response of neurons to these fatty acids or a combination of both.

Fig. 2

Mechanism of hypothalamic inflammation induced by saturated fats leading to the disruption of appetite control. High-saturated-fat diet promotes saturated fatty acids accretion in the hypothalamus, resulting in activation and accumulation of microglia and increased TNF-α production, leading to neuronal stress. The activation of IKKβ/NFκB leads to the expression of SOCS3, which inhibits leptin and insulin signaling, leading to increased food intake.

A high-fat diet (39% of kcal from lard) and TNF-α can activate neuronal IKKβ/NF-κB pathway, possibly through receptor-independent intracellular organelle stresses and cytokine receptors, respectively. It has been demonstrated that the activation of IKKβ/NF-κB can cause leptin and insulin resistance in the CNS via the expression of the SOCS3, a known inhibitor of insulin and leptin signaling (Fig. 2). Suppression of IKKβ on the AGRP neurons interrupts the activation of IKKβ/NF-κB pathway and improves leptin and insulin signaling, protecting against obesity [3].

Besides the mentioned proinflammatory effects of saturated fats on the hypothalamus, other dietary fatty acids can foster distinct inflammatory responses. Partially swapping lard with flax seed oil (rich in polyunsaturated fatty acid C18:3) or olive oil (rich in monounsaturated fatty acid C18:1) reversed diet-induced obesity (DIO) in mice, showing a reversal of hypothalamic inflammation, systemic insulin resistance and body adiposity. Also, ICV injections of ω3 and ω9 fatty acids modify feeding behavior and reduce food intake and adipose tissue accumulation. Additionally, these results showed improvement in insulin/leptin signaling and enhanced anorexigenic and prothermogenic neuropeptides POMC/CART expression while reducing the expression of anabolic neuropeptides NPY and melanin-concentrating hormone [19]. This study showed similar effects between linolenic (ω3) and oleic (ω9) fatty acids. The authors suggest that these fatty acids act upon the unsaturated fatty acid receptor GPR120, which shows increased expression in the NPY neurons [19]. G-protein coupled receptor 120 is activated by unsaturated fats, initially found in monocytes, and represses tissue macrophage inflammation, owing to its insulin-sensitizing and anti-inflammatory actions through β-arrestin 2/TAB1, blocking the TLR4 and TNF inflammatory pathways [20]. Cintra et al. found that despite similar outcomes, ω9 and ω3 fatty acids had some differences in reducing the mediators of inflammation. For instance, ω9 was more potent in reducing iNOS and IL-6, and ω3 fatty acids were more powerful in reducing pJNK. Both reduced TNF-α to a similar degree, and they both showed increased anti-inflammatory cytokine IL-10 [19]. This study shows that a high-fat diet with partial substitution of lard for olive oil or flax seed oil can reverse the hypothalamic inflammation and metabolic alterations seen in DIO.

Similarly, docosahexaenoic acid (DHA) (C22:6n-3) exhibits a potent anti-inflammatory effect on the brain, able to reduce the production of TNF-α and IL-6 by activated microglia [21]. Another study confirmed the protective effect of a high-fish-oil diet (rich in DHA) on hypothalamic metabolic inflammation [22]. However, a high-soy-oil diet (rich in ω 6 PUFA) showed a proinflammatory effect on the hypothalamus of Wistar rats and increased body weight similar to the effects of a high-saturated-fat diet [22]. Likewise, cohort studies analyzing trans-fatty acid intake have linked it to systemic inflammation, endothelial dysfunction and increased risk of stroke [[23][24]]. In addition, a diet rich in trans-fats during pregnancy and lactation can induce a hypothalamic proinflammatory state and impair central insulin signaling in the offspring [[4][5]].

These recent pieces of evidence establish a likely cause and effect relationship between hypothalamic inflammation and the development of metabolic diseases such as obesity. It seems that environmental factors, such as dietetic cues, can trigger central inflammation and alter the body's metabolic homeostatic system.