FGF21 serum levels are related to insulin resistance, metabolic changes and obesity in Mexican people living with HIV (PLWH)

Abstract

Background Antiretroviral therapy has significantly improved prognosis in treatment against HIV infection, however, prolonged exposure is associated to cardiovascular diseases, lipodystrophy, type 2 diabetes, insulin resistance, metabolic alteration, as obesity which includes the accumulation of oxidative stress in adipose tissue. FGF21 is a peptide hormone that is known to regulate glucose and lipid metabolism. FGF21 is expressed and secreted primarily in the liver and adipose tissue, promoting oxidation of glucose/fatty acids and insulin sensitivity. Alterations in FGF21 may be associated with the development of insulin resistance, metabolic syndrome and cardiovascular disease. We hypothesized that FGF21 protein levels are associated with metabolic abnormalities, placing special attention to the alterations in relation to the concurrence of overweight/obesity in people living with HIV (PLWH). Design Serum FGF21 was analyzed in 241 subjects, 160 PLWH and 81 unrelated HIV-uninfected subjects as a control group. Clinical records were consulted to obtain CD4+ cell counting and number of viral RNA copies. Serum FGF21 levels were tested for correlation with anthropometric and metabolic parameters; glucose, cholesterol, HDL, LDL, VLDL, triglycerides, insulin and indexes of atherogenesis and insulin resistance (HOMA). Results The participants were classified into four groups: (i) PLWH with normal weight, (ii) PLWH with overweight/obesity, (iii) HIV-uninfected with normal weight, and (iv) HIV-uninfected with overweight/obesity. Insulin levels were higher in normal-weight PLWH than in the HIV-uninfected group but not statistically significant, however, for the overweight/obesity PLWH group, insulin levels were significantly higher in comparison with the other three groups (p<0.0001). For FGF21, serum levels were slightly higher in the overweight/obesity groups in both patients and controls. In HIV-infected subjects, FGF21 levels showed a strong positive correlation with triglycerides, insulin levels and insulin resistance with a p-value <0.0001. In the seronegative group, FGF21 was only correlated with weight and waist circumference, showing an important association of FGF21 levels with the degree of obesity of the individuals. Conclusion Insulin resistance and FGF21 elevations were observed in overweight-obese PLWH. FGF21 elevation could be viewed as a compensation mechanism as, in the control group, FGF21 correlations appeared to be confined to weight and waist circumference. This can be explained based on the action of FGF21 promoting the uptake of glucose in adipose tissue. In PLWH, FGF21 was low, possibly as a result of a change in adiposity leading to a metabolic disruption.

Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume

“…Consistent with the results observed in our study, others have also reported increased FGF21 levels in individuals with obesity and a positive correlation with adiposity, insulin, and triglycerides [37]. This paradox between the beneficial effects of FGF21 on metabolism and the observed augmented circulating levels in human adults with overweight and obesity might be explained by an "FGF21-resistant" state in these individuals [38].…”

“…Therefore, it might seem paradoxical that we observed a positive association between the plasma levels of FGF21 during the warm period and several markers of adiposity and cardiometabolic risk, including BMI, WC, visceral adipose tissue mass, insulin, HOMA‐IR, and cholesterol. Consistent with the results observed in our study, others have also reported increased FGF21 levels in individuals with obesity and a positive correlation with adiposity, insulin, and triglycerides [37]. This paradox between the beneficial effects of FGF21 on metabolism and the observed augmented circulating levels in human adults with overweight and obesity might be explained by an “FGF21‐resistant” state in these individuals [38].…”

The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model

“…As discussed above, conditions associated with overfeeding, including obesity, are also associated with increased systemic FGF21 levels. This has been shown consistently in humans and rodents fed a HFD, diets high in carbohydrates, and ketogenic diets (3,20,72,73,128), as well as humans with obesity (26)(27)(28)76) and in humans that have been acutely overfed (164). In many of these studies, mRNA and protein expression of FGF21 have consistently been shown to be increased in WAT in the setting of overnutrition (29,39,72), raising the possibility that Ad-FGF21 could be a source of circulating FGF21 in this context.…”

“…Serum FGF21 levels were also significantly elevated in subjects with metabolic syndrome (defined as having 3 or more of the following criteria: central obesity (waist circumference ≥ 80 cm in women and 90 cm in men), hypertriglyceridemia (fasting triglycerides ≥ 1/69 mmol/L), low HDL cholesterol (fasting HDL < 1.29 mmol/L in women and < 1.04 mmol/L in men), hyperglycemia (fasting glucose ≥ 5.6 mmol/L or taking oral hypoglycemic agents for the treatment of type 2 diabetes), or hypertension (sitting blood pressure ≥ 130/85 mmHg) ( 28 ). Plasma FGF21 levels were also measured in a separate cohort of men and women in Mexico (n=241), and also showed a positive correlation between serum FGF21 levels and body weight and waist circumference ( 76 ). Similarly, serum FGF21 positively correlated with BMI, waist circumference, and adiposity in healthy men and those with diabetes in Tanzania ( 77 ).…”

Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients – a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown

“…FGF21, a hepatokine with a key metabolic role in glucose and lipid homeostasis is also expressed in HIV patients. The detection of a high FGF21 serum level in these patients was associated with MetS, lipodistrophy, and severe steatosis (239)(240)(241). Given the strong correlations between FGF21 and metabolic parameters, FGF21 has been suggested as a possible prognostic marker to monitor HALS and its therapy as well as the ART-associated cardiovascular risk (242).…”