Obesity linked to mitochondrial dysfunction in GI tract, treatable by fat restriction
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I think the claim that obesity can be caused by lower metabolism is not something contentious, even though mainstream medicine will claim that it only happens in clinical hypothyroidism. The so-called idiopathic obesity in the general population (now affecting 40%+ of people) is claimed to be due to nothing more than the gluttony of said population, combined with not performing enough physical exercise. The study below demonstrates that obesity can be caused even in the context of normal caloric intake, if the mitochondria in the enterocytes lining the GI tract are not functioning properly. When there is such a GI tract mitochondrial dysfunction, the enterocytes cannot properly form/create chylomicrons, which distribute dietary fat to the peripheral tissues, where it usually is quickly oxidized by muscles and organs as fuel. In fact, muscles at rest oxidize predominantly fat. However, if that fat cannot reach the muscles the fat remains in the abdominal area (and if transported, it is exclusively to the liver), accumulating over time and causing the dreaded “central obesity” combined with liver diseases such as NAFLD/NASH/fibrosis/cirrhosis/etc. If that mechanism can explain obesity to a great degree then it matches perfectly with the lifestyle and diet of the Western population. Acute or chronic stress causes mitochondrial dysfunction by inhibiting blood flow to the GI tract, and cortisol has a direct mito-suppressive effect. In addition, there is myriad of chemicals in our food and drinks that act as metabolic/mitochondrial inhibitors. PUFA is obviously a major mitochondrial inhbitor, but there are more cunning ones used as food additive and approved as “safe” by the regulatory agencies. Things such as emulsifier, dyes, artificial flavors, silicon dioxide, talc, titanium dioxide, etc are all known mitochondrial inhibitors and a majority of the Western population ingests at least one such inhibitor on a daily basis. Conversely, the study suggests that things like niacinamide, aspirin, quinones, thyroid, saturated fats, sucrose, etc would be good approaches to restoring mitochondrial function and thus resolving, or at least stopping, the obesity process. Interestingly, feeding a fat free diet to the animals used in the study was also able to reverse the mitochondrial dysfunction and the accumulation of lipids in the GI tract. This matches quite well with Peat’s recommendations to lower fat intake in cases of obesity, or chronic diseases.
https://www.nature.com/articles/s41586-023-06857-0\
“…Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. **Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes**, which shows that the accumulating lipids derive mostly from digested fat.”
Warning: High Levels of Niacin (Vitamin B3) Linked to Heart Disease
“…The researchers studied the function of mitochondria – organelles acting as powerhouses of the cell – in enterocytes, cells that line the intestine and specialize in the absorption and transport of nutrients from digested food. They found that disruption of mitochondrial function in the intestines of mice caused abnormal accumulation of dietary fat in enterocytes and impaired delivery of lipids to the peripheral organs. A key finding of the study was that, when mitochondria did not function properly, enterocytes showed impaired packaging and transport of lipids in the form of chylomicrons. Chylomicrons are crucial carriers of dietary fats, and their proper formation and transport are essential for the absorption of nutrients. “This discovery marks a significant leap forward in understanding the crucial role of mitochondria in dietary lipid transport and metabolism,” said Dr Chrysanthi Moschandrea, the lead author of the study. The implications of this discovery go beyond the realm of basic research. “These findings provide new perspectives for the better understanding of the gastrointestinal symptoms in patients suffering from mitochondrial disease, and may also lead to new therapeutic approaches,” added Professor Aleksandra Trifunovic.”
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Haidut what are your thoughts on PPAR gamma antagonists for diabetes and obesity? PPAR gamma knockout mice have no adipose tissue. Niacinamide seems to downregulate PPAR gamma while niacin seems to upregulate it.
This study (a bit biased on SFA) claims palmitate activates it through NNMT which depletes NAD plus and niacinamide can counter that. And since SAM is what is needed for NNMT would increasing homocysteine for a while through depleting methyl donors w niacinamide etc be a good trade off ?
https://pubmed.ncbi.nlm.nih.gov/37212549/
Niacin also increases PPAR gamma , Im wondering how the mechanism differs for niacinamide (Is it abrogating PPAR gamma transactivation only when palmitate induced or is NAD plus the deciding factor)
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G GuantanamO'Shea referenced this topic on
