T-cell mitochondria exhibit a functional decline with obesity that is aggravated with weight loss

Abstract

Objective: Resistance to weight loss (WL) and propensity to weight regain are major challenges to achieve long-term metabolic health for people with obesity. It is yet to be determined whether mitochondria (MITO) play a role as a counter regulatory mechanism that impedes diet-induced WL that could contribute to slowing of WL and eventually, a WL plateau. This study aimed to 1) elucidate differences in MITO sensitivity to energy demand by peripheral mononuclear cells (PBMCs) in subjects with and without obesity, and 2) compare MITO respiratory capacity in subjects with obesity (OB) who were in phases of active weight loss (OB-WL), plateau (OB-PL), or regain (OB-RG). Methods: Fresh blood samples were collected from fasted participants with BMI of 30-56 kg/m2 at either their baseline, or their 6-month, or 12-month visit following 24-weeks of behavioral WL intervention. Blood was also collected from healthy weight-control participants (HWC, n=11) (BMI of 18.5-24.9). PBMCs were isolated through density gradient centrifugation, and CD3+ (T-cell) and CD14+ (monocytes) were subsequently separated though magnetic activated cell sorting. MITO function of non-permeabilized cells was assessed by Agilent Extracellular Flux Analysis (XFe), and MITO sensitivity to energy demand was assessed using the Oroboros high-resolution respirometer (O2K) in permeabilized cells. To determine the phase of WL at each visit, body weight trajectories were tracked for each participant throughout 18 months using a remote electronic scale. Threshold regression modeling was used to determine if the participant was in OB-WL (BW loss ≥0.5lbs/wk, n=7), OB-PL (±0.25lbs/wk, n=10), or OB-RG (BW gain ≥0.5lbs/wk, n=6). Results: There was a consistent reduction in MITO capacity of T-cells in the OB group (2.0±0.6 pmol O2/106 cells) compared to HWC (2.8±0.8), in both non-permeabilized (P=0.01) and permeabilized cells (p=0.02), that was more pronounced when inhibiting complex I (P=0.02). Maximal membrane potential was also lower in the OB group (P<0.01), and membrane depolarization with ADP tended to be more sensitive in the OB group, but differences were not statistically significant (p=0.17). No significant differences were found in monocyte MITO function between the two groups.We found lower MITO respiratory capacity in T-cells from the OB-PL (1.4±0.4) and OB-RG (1.6±0.8) groups relative to OB-WL (2.5±0.4). T-cell bioenergetic health index negatively correlated with the slope of % weight loss calculated using the weight loss trajectory (r=-0.661, p=0.027). Conclusions: T-cells exhibit reduced MITO respiratory capacity in participants with obesity at baseline compared to those in the normal weight range. MITO respiratory capacity was further reduced in participants at the WL-PL. These findings suggest that reductions in MITO respiratory capacity are exacerbated rather than improved in response to diet-induced WL, potentialy indicating resistance to further WL at a plateau promoting regain. T32 HL007028 (APV), K01 HL164761-01 (APV), P30DK035816 (APV), R01DK089036 (EAS) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.