Can a Western high-fat diet lead to painful neuropathy?

STANDFIRST:

Neuropathy is a painful and potentially crippling disorder that is common in diabetic patients, but often affects individuals with obesity, yet the reason for this is not well understood. In this issue, Boyd et al. reveal that a diet enriched in ω-6 polyunsaturated fatty acids (PUFAs) is sufficient for triggering peripheral neuropathy in mice, which can be reversed by enriching the diet with ω-3 PUFAs instead. These findings may help explain the high incidence of neuropathies in non-diabetic patients with diet-related obesity, while providing a potential target for the prevention and treatment of this metabolic and neurological disorder.

Primary sensory neurons detect various stimuli from the periphery, including those that may cause pain, and relay this information to the central nervous system, where it will be interpreted as painful or non-painful. The cell bodies of these primary sensory neurons lie in dorsal root ganglion (DRG), which are neuronal bundles that lie just outside the spinal cord. Each sensory neuron is composed of two axons: one of them projects towards the periphery, often terminating in the epidermis of the skin, where it collects the information to be relayed; the other makes a short trip into the spinal cord, where the signal is passed to a second-order neuron and travels to the brain (Fig. 1a) ¹.

FIGURE 1: High fat diet induced painful neuropathy and its treatment by low fat diet in mice.

Dorsal root ganglia from (a) homeostatic and (b) painful neuropathy induced by a diet high in ω-6 PUFAs (H6D). H6D-induced neuropathic pain can be blunted by a PLA2g7 inhibitor or by replacement with a diet high in ω-3 PUFAs (H3D). Whether a H3D can resolve painful neuropathy remains to be seen.

Painful peripheral neuropathies are caused by damage to the axons projecting towards the periphery and are marked by two phenomena (Fig. 1b). First, the distal fibers of many sensory neurons are damaged and often destroyed. This loss of nerve endings that is common in diabetic neuropathy, and also following chemotherapy, can cause debilitating weakness and often numbness, especially in the hands and feet. Second, the nearby neurons whose fibers remain intact become hypersensitive. For some patients, even putting on a shirt can be torturous as the fabric stimulates the fibers of these nociceptors, causing hyperexcitability. Furthermore, activation of low-threshold mechanoceptors may trigger pain after neuropathy, termed as tactile allodynia or touch-induced pain. While the symptoms of neuropathy are well known, a better understanding of how to prevent and treat these disorders is desperately needed ².

Although diabetes is a common risk factor for neuropathy development², it is strikingly prevalent among individuals with obesity that have normal blood glucose levels, hinting at a yet unknown mechanism for developing this condition³. Here, Boyd et al. demonstrate that a diet enriched with ω-6 PUFAs –which, when consumed in excess, are linked to cardiovascular risk– leads to neuropathy⁴. Specifically, feeding mice during 8 to 24 weeks with a high ω-6 PUFA diet (H6D) led to persistent mechanical and thermal hypersensitivity compared to a low ω-6 PUFA diet (L6D). Mice exposed to the H6D also developed signs of peripheral neuropathy, as indicated by loss of intraepidermal nerve fibers and increased neuronal expression of the transcription factor ATF3, a well-known marker for nerve injury⁵. Furthermore, electrical recordings from the remaining intact fibers using ex vivo skin-nerve preparations evidenced spontaneous firing and hyperexcitability in these nerves.

Genetic mouse models of diabetes become hyperglycemic and gain substantial weight, while also developing the typical symptoms of neuropathy. Boyd et al. compared their H6D mice to a transgenic mouse model of diabetes⁴. Notably, the H6D fed mice did not display any signs of hyperglycemia, nor did they outweigh their control counterparts. Additionally, when diabetic mice were switched to a H6D, their pain sensitivity was intensified, suggesting that these mechanisms are distinct and additive in nature.

The cause of this neuropathy seemed to be the production of pronociceptive lysophospholipids, rather than diabetes. These lipids can cause demyelination and neuropathic pain⁶. High fat diets (HFD) are known to increase levels of arachidonic acids (AA) and linoleic acids (LA), both of which are pronociceptive⁷ and can be further broken down into these lysophospholipids by an enzyme called phospholipase A2 (PLA2). The authors further demonstrated that both LA and AA were upregulated in DRGs after 8 weeks of H6D exposure, and that PLA2 activity was increased in DRG homogenates. Strikingly, among the 21 PLA2 isoforms examined in this study, only PLA2g7 was enriched in DRG neurons and accounted for 80% of PLA2 activity in these neurons. Furthermore, local pharmacological inhibition of PLA2g7 with darapladib (currently under clinical investigation for non-pain conditions) attenuated H6D-induced nociceptive hypersensitivity.

Intriguingly, switching back from a H6D to a diet enriched in ω-3 PUFAs (H3D) –which are linked to cardiovascular protection– reversed nociceptive hypersensitivity. Found in foods such as fish and flax seeds, ω-3 PUFAs are broken down into “specialized pro-resolving mediators (SPMs)”, including resolvins, protectins, and maresins⁸. Resolvins have been demonstrated to reduce inflammation and combat pain at very low doses⁹. It is especially promising that in a separate experiment, the mice receiving H6D plus ω-3 PUFA supplementation showed signs of recovery, since supplementation is much easier to prescribe clinically than dietary change.

While this study sheds light into the impact of diet on chronic pain management, some questions remain to be answered. Of note, the mice in this study had only been on a modified enriched ω-6 PUFA diet for eight weeks, and the diets they consumed were highly skewed towards these lipids. Whether lowering ω-6 PUFA intake over time would lead to significant improvements in neuropathic pain symptoms in humans remains unknown. Mechanistically, understanding the specific contributions of different types of lysophospholipids, such as lysophosphatidylcholine (LPC 18:1 and LPC 16:0)¹⁰ to pain and neuropathy will be of great interest for future investigations. It will also be of great therapeutic importance to test whether ω-3 PUFA supplementation or SPMs are able to reverse and resolve painful neuropathy in humans (Fig. 1).

As a final thought, Western diets, which are associated with obesity, are characterized by a major imbalance between ω-6 and ω-3 PUFA content. However, the NIH Peripheral Neuropathy Fact Sheet does not currently include ω-6 PUFA intake among the risk factors for developing neuropathy (cite https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet)¹¹. This study may raise awareness on the issue, highlighting the need for considering diet as part of the therapeutic program for pain management. This comprehensive and elegant study from Dr. Hargreaves’ group could serve as the foundation for new clinical trials and ultimately provide new avenues for treating neuropathies in the clinic. Moving forward, both ω-3 PUFA supplementation and darapladib should be investigated for potential use against these neuropathies.