Obesity by High-Fat Diet Increases Pain Sensitivity by Reprogramming Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia

Abstract

Obesity is a significant health concern as a result of poor-quality diet, for example, high-fat diet (HFD). Although multiple biological and molecular changes have been identified to contribute to HFD-induced pain susceptibility, the mechanisms are not fully understood. Here, we show that mice under 8 weeks of HFD were sensitive to mechanical and thermal stimuli, which was coupled with an accumulation of branched-chain amino acids (BCAAs) in lumbar dorsal root ganglia (DRG) due to local BCAA catabolism deficiency. This HFD-induced hyperalgesic phenotype could be exacerbated by supply of excessive BCAAs or mitigated by promotion of BCAA catabolism via BT2 treatment. In addition, our results suggested that HFD-related pain hypersensitivity was associated with a pro-inflammatory status in DRG, which could be regulated by BCAA abundance. Therefore, our study demonstrates that defective BCAA catabolism in DRG facilitates HFD-induced pain hypersensitivity by triggering inflammation. These findings not only reveal metabolic underpinnings for the pathogenesis of HFD-related hyperalgesia but also offer potential targets for developing diet-based therapy of chronic pain.

Defective branched‐chain amino acid catabolism in dorsal root ganglia contributes to mechanical pain

“…Consistent with our recent study (Lian et al , 2022), mice under 16 weeks of HFD exhibited reduced nociceptive thresholds to both mechanical and heat stimuli by von Frey test and Hargreaves test (Fig 1A–C), and this increased sensitivity to mechanical stimuli was associated with an accumulation of BCAAs in lumbar DRG and a downregulation of PP2Cm, a key enzyme in the BCAA catabolic pathway (Fig 1D–F). Adult DRG neurons are metabolically and physically supported by glia cells (Tasdemir‐Yilmaz et al , 2021).…”

“…Branched‐chain alpha‐ketoacid dehydrogenase (BCKDH) complex, the rate‐limiting enzyme of the pathway, is activated by a mitochondrial localized 2C‐type serine–threonine protein phosphatase (PP2Cm), which dephosphorylates and thus activates BCKDH (Lotta et al , 2016). Recently, we reported BCAA catabolism deficiency in DRGs of HFD obese mice due to downregulated PP2Cm expression and increased BCKDH phosphorylation, which resulted in a hyperalgesia phenotype (Lian et al , 2022). Yet, it remains to be clarified how BCAA catabolism controls pain behaviors.…”

“…SNI and CFA represent different types of chronic pain (i.e., neuropathic and inflammatory pain) and are usually applied in the researches of mechanical pain (Liu et al, 2018;Segelcke et al, 2021). Our prior study demonstrated that impaired BCAA catabolism could induce inflammation in DRG (Lian et al, 2022); however, it is not necessary that inflammation could in turn change BCAA catabolism. Indeed, in the present study, we found that CFA-related inflammation did not alter BCAA catabolism in DRGs, while neuropathic injury induced defective BCAA catabolism.…”

Bcat2‐Mediated Branched‐Chain Amino Acid Catabolism Is Linked to the Aggravated Inflammation in Obese with Psoriasis Mice

“…discovered that HFD‐fed mice exhibit BCAA accumulation in dorsal root ganglia due to catabolic defects, linking to HFD‐related pain sensitivity. [ 31 ] HFD feeding did not raise circulating BCAAs levels in insulin‐resistant diet‐induced obese mice, according to Lee study. [ 32 ] For upcoming experiments, we aim to enhance our understanding of the relationship between BCAAs and psoriasis by both supplementing and restricting BCAAs in the animal diet, and conducting clinical sample analyses.…”

Effect of Circadian Rhythm Disturbance on the Human Musculoskeletal System and the Importance of Nutritional Strategies

“…Several studies have suggested that anti-inflammatory foods, such as those found in the Mediterranean diet (vegetables, fruits, fish, fish oils, legumes, olive oil, and plant-based proteins), are best for relieving the inflammation and pain associated with chronic musculoskeletal disorders and diseases [ 113 ]. On the contrary, an excessive fat diet was found to increase nociceptive responsiveness and enhance pain sensation in an animal study on knee arthritis [ 115 ].…”