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Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

Abstract: The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6 J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity.

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Alex’s Notes: It is well-known that the hypothalamus is the body’s master regulator when it comes to energy homeostasis. One of the central players in alerting the hypothalamus to the body’s nutritional status is leptin, a hormone secreted by adipocytes (fat cells) that alert the hypothalamus to how much energy the body has stored away. Its concentration also fluctuates, albeit to a much smaller extent, with caloric intake. Ultimately, as leptin goes up, food intake and body weight go down.

Ironically, being obese causes a state of leptin resistance, making the anorexic hormone not work at a time when its functions are needed most. This resistance is similar to insulin resistance in that the body (or in leptin’s case, the hypothalamus) becomes resistant to the hormone, making more of it needed to exert an effect. Many answers to why this occurs have been proposed, one of which is an abundance of saturated fat in the blood.

Palmitic acid (PA; C16:0) is the most abundant saturated fatty acid in the blood. It is also the most abundant saturated fatty acid in the diet, with the richest sources being palm oil, beef tallow, lard, bacon grease, butter, and chicken fat. However, research has shown that this fatty acid can readily cross the fat-soluble blood brain barrier in a linear fashion, meaning that greater concentrations in the blood increase the amount that reaches the brain. In fact, the referenced study showed that 40% of infused palmitic acid that enters the blood is incorporated into brain tissue within 45 seconds. These results in rats have been confirmed and expanded upon in humans, with uptake and accumulation of palmitic acid within the brain being more pronounced in persons with metabolic syndrome compared to those without, and this appears to be reversed by weight reduction.

The issue with its accumulation is that some evidence shows it to promote inflammation within the brain (interestingly, unsaturated fatty acids do not have this effect and DHA actually inhibits saturated fatty acid stimulation of inflammation in a dose-dependent manner). To expand upon these findings, the current study investigated hypothalamic leptin sensitivity, signaling, and inflammation in response to palmitic acid administration in mice.

The mice were maintained under normal mouse conditions with normal mouse chow, with an icv cannula inserted into the brain. The mice were randomly divided into four groups:

  • PA + leptin (PAL)
  • PA + placebo (PAP)
  • Placebo + leptin (PL)
  • Placebo + placebo (PP)

The PA or placebo was injected twice per day for two days. On the third day, the mice received a final injection followed by leptin or a placebo 1-hour afterwards. This happened on three occasions, each separated by a half-week washout period, and on each of these occasions a different test was performed shortly after the leptin/placebo injection. The first was monitoring of weight and food intake for 24 hours; the second was an oral glucose tolerance test; and the third was death and collection of the liver and brain for analysis.

So what can elevated palmitic acid do for you?

As would be expected given our understanding of leptin’s role in energy regulation, the PL mice experienced a dramatic reduction in food intake and body weight (-11.7%). Additionally, analysis of several genes involved in glucose and lipid metabolism within the liver showed that leptin reduced expression of PEPCK, G6Pase, and GLUT2 (signifying reduced gluconeogenesis and export of glucose into the bloodstream) as well as FAS, SCD1, and HMG-CoA reductase (signifying reduced fatty acid and cholesterol synthesis). Finally, leptin induced the expression of tyrosine hydroxylase (TH) within the brain, which is the rate-limiting step in the synthesis of the catecholamines, thus indicating leptin increased sympathetic outflow.

When palmitic acid was administered beforehand (the PAL group), every single one of these effects was either reduced in magnitude or completely abolished all together. This was exemplified during the glucose tolerance test where the PAL mice showed significantly elevated blood glucose levels both at fasting and 30 minutes after the glucose load, indicating that palmitic acid impaired the ability of leptin to maintain normal blood glucose levels. This may have occurred, in part, to the blunting of leptin’s reduction of PEPCK, G6Pase, and GLUT2, which would indicate that the liver continued to make glucose from other molecules such as amino acids and glycerol and pump it into the bloodstream despite hyperglycemia. This is characteristic of hepatic insulin resistance and a central feature of type-2 diabetes and fatty liver diseases.

It is clear that palmitic acid interferes with leptin’s ability to do its job, and to figure out why, the researchers also performed testing for gene expression in the hypothalamus. When palmitic acid was not present (PL group), leptin significantly increased the expression of pJAK2, pSTAT3, pAkt, and pFOXO1. This was no surprise, as both the JAK2-STAT3 and Akt-FOXO1 pathways are necessary for leptins regulation of energy metabolism. For example, FOXO1 over-expression leads to hyperphagia and orexigenic effects, and leptin regulates and reverses these effects by promoting the binding of Akt to FOXO1. However, when palmitic acid was present (PAL group), the expression of the JAK2-STAT3 and Akt-FOXO1 pathways never occurred.

But how did palmitic acid interfere with leptin’s signaling? Something that only occurred in mice treated with palmitic acid was a significant elevation of several inflammatory cytokines such as TNFα and IL1-β, supporting the previously mentioned findings of other research showing that palmitic acid directly causes inflammation in the brain. Indeed, this inflammation could be a reason for the impaired JAK2-STAT3 and Akt-FOXO1 signaling in the brain.

What does this mean for us?

In a nutshell, the current study provides strong evidence that palmitic acid causes leptin resistance through increased inflammation that impairs the signaling of two key pathways by which leptin interacts with the hypothalamus. This in turn alters the central regulation of hepatic glucose and lipid metabolism.

These important findings demand that we ask ourselves how the implications translate to us. As mentioned previously, the amount of palmitic acid within the brain rises as concentrations within the blood increases. A notable caveat is that the palmitic acid cannot be esterified. Within the blood, esterified fatty acids are found within the triglycerides and phospholipids of circulating lipoproteins or chylomicrons. Thus, any palmitic acid that is consumed from the diet or created within the liver (de novo lipogenesis) will not enter the brain, at least not directly.

The non-esterified fatty acids that do cross the blood-brain barrier mostly come from stored adipose tissue as it releases the fatty acids into the bloodstream for use by the body. For palmitic acid, the amount released by adipocytes is directly proportional to the amount that is stored within them. And this is where diet comes into play. Mathematical modeling has shown that stored fat composition is significantly related to dietary fat consumption patterns, and that adipocyte composition reflects long-term dietary habits (around 2-3 years). In other words, your fat cells look like your diet did 2-3 years ago in terms of the percentage of calories consumed from the various types of fats.

Therefore, the implications for us are that a diet high in palmitic acid, which is the most abundant saturated fatty acid in animal-based fats, will lead to an increased storage of this fatty acid within adipose tissue. As the storage increases, more will be released into the bloodstream, leading to a greater amount being available to enter the brain and cause leptin resistance. This also nicely explains the leptin resistance experienced with obesity, as having a greater amount of adipose tissue will also lead to more plamitic acid release into the bloodstream.

When the above is considered along with other research showing that skeletal muscle fatty acid composition also directly relates to dietary intake, and that there is a proven association of high saturated fat content within muscle tissue and muscular insulin resistance, it does indeed seem prudent to limit animal-based saturated fats within the diet. However, we cannot say how much is too much, as we don't know at this point whether there is a threshold that must be crossed for dietary intake to have a significant influence on the composition of adipocytes, or if it is a linear relationship where less is better. Thus, it does seem more prudent to not become obese, so as to avoid having a ton of fat cells able to release palmitic acid into the bloodstream.

Keep in mind that this says nothing about the amount of fat within the diet, only the composition of that fat. Whether one chooses to follow a low-fat or high-fat diet, the focus should be on medium-chained saturated fatty acids (coconut, for example), omega-3 polyunsaturated fatty acids (fish and seafood), and monounsaturated fatty acids (avocados, olives, macadamia nuts, etc.). This would also help avoid problems with fat & carbohydrate food combinations and acute insulin resistance

 

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