This study provided a broader view of glucolipid metabolism in PHP1 based on a rather large cohort of Chinese PHP1 patients. By evaluating the metabolic indices and adipokine levels, we found that PHP1 patients who were overweight/obese presented with abnormal HOMA indices as well as TNFα and leptin levels, which have not been revealed in previous research concerning similar clinical issues.

In our study, the overall overweight/obesity ratio in PHP1 group and PHP1A, PHP1B subgroups were 36.7%, 42.8% and 34.3%, respectively, which were not significantly different from the normal control group. One of our previous researches found that the overweight/obese rate were 40% and 38% for 10 PHP1A/1C and 94 PHP1B patients, respectively, which were higher than the general population [7]. One recent large cohort survey recruited 2548 underage patients with severe obesity and conducted genetic analysis. Among them, 22 presented with early-onset obesity, and among whom 19 bore heterozygous GNAS mutation, revealing an unexpectedly high prevalence of loss-of-function GNAS mutation among junior obesity patients [11]. The small sample size may be responsible for the disparity between current study and previous research, which means that although the prevalence may seem similar, as one of the characters of AHO, overweight/obese can still be part of the concerning health problems for PHP1 patients.

Previous studies implicated the occurrence of higher incidence of underage obesity [5] and early-onset obesity as early as the first year of life [8] among PHP1 especially PHP1A patients, which was not observed in our study since the number of patients with/without overweight/obese was not significantly different in different age subgroups. One reason may be that underage patients, especially infants with early-onset PHP1 related symptoms were referred to specialized hospitals, leading to a selection bias in our study. The bias also resulted in a relatively elder age distribution in the underage group, whose diet and eating behavior had been greatly affected by education and dietary regulation rather than their underlying genetic defects, which may be another possible reason for the unobvious overweight/obese prevalence in the underage PHP1 patients.

To date, there are only a few case reports describing hyperinsulinemia and impaired glucose tolerance in PHP1 patients [2,3,4]. Two recent cohort studies evaluated the glucometabolism in adult and underage PHP1A patients, revealing glucose tolerance impairment, β-cell dysfunction and delayed appearance of blood glucose peaks, slower rate of postprandial blood glucose decline in these two groups respectively [5, 6], all of which indicated deeper investigation into the reason and risk factors of the underlying abnormal glucometabolism in PHP1 patients.

While pancreatic β-cell function was described to decrease in PHP1A patients in previous research [5, 6], the higher HOMA-β observed in the in overweight/obese subgroup of PHP1 could be seen as a compensational increase in β-cell function under glucolipid metabolic stress during the early stage of type 2 diabetes according to what Bonner-Weir et al. had described [12, 13], which were later proved by Puff et al. [14]. Although previous studies have confirmed that the effects of some G protein coupled receptor (GPCR) medicating incretin lost their insulin stimulating function in Gsα knockout mice [15], the present study showed no difference of glucometabolism indexes between different molecular subtypes of PHP1 patients. The abnormality in overweight/obese but not in certain molecular subtype of PHP1 patient suggested that the impact of body fat accumulation exceeded the deviant expressed GNAS in insulin stimulation, inducing the compensation of β-cell function in these patients. However, only fasting blood glucose and fasting insulin were evaluated in our study. For further investigation, OGTT, IVGTT and glucose-insulin clamp test could act as a more effective and sensitive method for glucometabolism evaluation in PHP1 patients in the future.

In our study, PHP1 patients presented with unparticular serum lipid levels comparing with normal control group, though TC, LDL-C, and HDL-C levels were significantly lower than those in the PHPT group. The correlation of high PTH concentration and hyperlipidemia have only been observed in PHPT population [16], while in PHP1, the defected GPCR pathway may be a concerning factor for the non-responding GPCR-dependent lipolysis pathway of PTH [16]. The medication of calcitriol in PHP1 patients could also influence the lipolysis of lipoprotein lipase (LPL) [17], which eventually resulted in a seemingly normal level of serum lipid level in PHP1 patients.

Analysis on leptin levels revealed the relationship between BMI and leptin which was observed to be significantly higher in overweight/obese subgroup of PHP1 patients. Apart from its correlations with obesity [18], it’s also believed that leptin could serve as a regulator of satiety mediated by GPCR in hypothalamus [19]. But the difference in LAR rest between BMI-based subgroups but not molecular subgroups suggested that the impact of body fat accumulation on peripheral leptin level may out-weighted the negative feedback regulation of the leptin-melanocortin pathway due to the malfunction of Gsα. The BMI related differences in LAR further suggested the possible insulin resistance, as previous investigation on elder female and severely obese population have associated higher LAR with worse insulin sensitivity [20, 21], and the similarity in LAR between PHP1A and PHP1B group could be explained by the indifferent BMI of them.

The PHPT group in our research preserved a significantly higher level of leptin than the other two groups. First of all, the elder age in the PHPT patient group may serve as an unneglectable reason for their higher BMI and the alteration in glucolipid metabolic features. Moreover, Maetani et al. found that within a rather large sample study, the relatively high blood 25OHD level had a correlation with low leptin level [22], suggesting that the difference in 25OHD in this study may be responsible for the difference in leptin between PHP1 and PHPT group. One recent in vitro study found that the leptin expression to be elevated in parathyroidectomized PHPT tissues, and PTH could be further produced when leptin was taken up [23]. Therefore, elevated leptin may as both the result of PTH induced fat accumulation and the stimuli on PTH production, thus contributing to the “PTH elevation-weight gain-leptin expression” cycle, which will aggravate glucolipid metabolism abnormality.

In our study, FGF21 levels were significantly higher in PHPT than in the other two groups. The correlation of age and FGF21 level [24] could explain the relatively higher FGF21 level in PHPT group. Although in PHP1 patients, due to the imprinting defect of β-adrenergic receptor in BAT [25], the cold stimuli on BAT via the β-adrenergic receptor-cAMP pathway [26] was weakened caused by the decreased expression/dysfunction of Gsα, presented as impaired elevation in FGF21 secretion. But the speculation still needs to be verified by further experiments.

Our findings showed significantly lower TNFα levels in the PHP1 and PHPT group than in the normal control group. Previous research found a significantly lower serum TNFα level in the vitamin D supplementary group comparing with the control group within a cohort of type 2 diabetes patients [27], suggesting that the vitamin D supplementation may have contributed to this difference. Furthermore, a newly published research involving meniscus injury induced osteoarthritis (MIO) model mice have observed a significant decrease in TNFα in PTH(1–84) treated MIO mice chondrocyte in vitro [28]. Considering the anti-inflammatory effect of PTH, the elevated serum PTH level could be a plausible reason for a lower peripheral TNFα concentration in both PHP1 and PHPT patients. But it is worth noting that the lowering of only TNFα should not be interpreted as the sign of a lower inflammation grade in PHP1 than in healthy population. Subsequent studies involving more factors are needed in order to provide a complete picture of the abnormal glucolipid metabolism and chronic inflammatory response due to overweight/obesity in PHP1 and PHPT patients.

Some limitations of our study should be mentioned. First of all, due to the rarity of the disease and the selection bias, the cohort of PHP1 was rather small, and the age was relatively elder, making the difference between obese/non-obese as well as underage/adult not as apparent as it was described in previous studies. The selection of the detected adipokines was mostly based on the general knowledge over obesity. Further analysis on more BAT-specified adipokines is needed for a deeper understanding on the influence of GNAS molecular defection on the function of adipose tissue.