Effects of lifestyle modification and metformin on irisin and FGF21 among HIV‐infected subjects with the metabolic syndrome

Abstract

Summary Objective Few studies have investigated irisin and FGF21 to elucidate the role of these hormones to regulate ‘beiging’ in HIV-infected patients. Design Fifty HIV-infected subjects with the metabolic syndrome were previously recruited and randomized to receive lifestyle modification (LSM) and/or metformin over 12 months. In the current study, we assessed FGF21 and irisin at baseline and after intervention. In addition, we assessed circulating FGF21 and irisin in relationship to brown adipose tissue (BAT) gene expression in dorsocervical subcutaneous fat biopsies from 13 HIV-infected subjects. Results At baseline, prior to intervention, HIV-infected subjects demonstrated increased log FGF21 (2·13 ± 0·06 vs 1·98 ± 0·05 pg/ml, P = 0·05) and log irisin (0·33 ± 0·02 vs 0·17 ± 0·04 μg/ml, P = 0·003) compared with healthy controls well matched based on waist circumference. After 12 months, HIV-infected subjects randomized to LSM demonstrated a relative reduction in FGF21 compared with those not randomized to LSM (−10 [−35,22] vs 40 [0,94] %change, P = 0·01). Changes in FGF21 were inversely associated with improved parameters of energy homoeostasis, including increased REE (ρ = −0·34, P = 0·046) and max VO2 (ρ = −0·38, P = 0·02), and reduced RQ (ρ = 0·40, P = 0·02) among all HIV-infected subjects. Increased UCP-1 (r = 0·75, P = 0·003), DIO2 (r = 0·58, P = 0·04) and CideA (r = 0·73, P = 0·01) gene expression in dorsocervical fat was significantly associated with FGF21 in HIV-infected subjects. Conclusion HIV-infected subjects with metabolic complications demonstrate increases in FGF21 in relationship to BAT gene expression. Relative reductions in FGF21 in those receiving long-term LSM relate to overall improvements in energy expenditure parameters. In contrast, irisin levels are elevated in HIV-infected subjects, but are not influenced by LSM nor associated with BAT gene expression.

New insights into the effects of irisin levels in HIV-infected subjects: correlation with adiposity, fat-free mass, and strength parameters

“…Levels of irisin also correlate The effects of increased FGF21 may be to promote increased expression of brown adipose tissue genes in a unique ectopic adipose depot. In contrast, irisin levels are elevated in individuals infected with HIV but are not influenced by lifestyle modifications or associated with brown adipose tissue gene expression (13).…”

“…In addition, irisin correlated positively with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), age, cholesterol ratio, and BMI in patients with gestational diabetes (12). Furthermore, irisin levels are elevated in individuals with HIV compared with those without HIV and are unaffected by lifestyle modifications, including exercise (13). Therefore, the available data regarding irisin and body composition in humans are inconclusive, especially in HIV-infected subjects.…”

Fibroblast Growth Factor 21 As an Emerging Therapeutic Target for Type 2 Diabetes Mellitus

“…revealed that 1‐week metformin treatment significantly improves glucose tolerance while decreases plasma FGF21 in new‐onset type 2 diabetes patients . Another study has demonstrated that there is no effect of metformin on FGF21 levels in HIV‐infected subjects with metabolic syndrome after 1‐year metformin therapy . In view of these findings, whether the in vivo regulation of FGF21 production by metformin is time dependent and whether metformin differentially regulates FGF21 expression in different stages of diabetes remain to be further elucidated.…”

“…It is worth noting that within the limited sample size, the majority of subjects were on stable metformin therapy prior to and throughout the whole treatment period in both studies. Hence, the effects of LY2405319/PF‐05231023 on glycemic control may be masked when dosed on top of metformin, especially the interaction between metformin and FGF21 has been revealed . It is also possible that those FGF21 analogs mainly regulate lipid metabolism and indirectly influence insulin sensitivity and glucose homeostasis in human, thus a longer period of time should be required to manifest the effects on glycemic control.…”

FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs

“…However, it has been also reported that the administration of metformin to human subjects with T2D for 1 week led to decreased serum FGF21 levels (Zhang et al 2013b). Serum FGF21 levels in HIV-infected subjects treated with metformin for 12 months were not significantly different from those in the placebo group (Srinivasa et al 2015). These discrepancies could be attributable to differences in patient selection, experimental analyses, or duration of metformin treatment.…”