HIIT has been confirmed to reduce VAT and relieve metabolic syndrome effectively [1, 5,6,7]. However, individual differences between subjects are large [1]. A previous meta-analysis found that the effect of HIIT on reducing VAT is evident in subjects with obesity or overweight but weak in normal weight subjects [5]. This phenomenon may be related closely to the difference between obesity phenotypes in adipose catabolism. Previous experiments have found that the fat loss effect of HIIT is related to the activation lipolysis [26,27,28, 31]. Because gene polymorphisms underlie individual differences in food intake, PA and adipose metabolism, we hypothesised that OP and OR individuals show different adaptive changes to HIIT, especially in lipolysis regulated by the SNS.

We compared how 12 weeks of HIIT affected VAT loss in OP and OR rats, as well as how this training affected catecholamine-regulated lipolysis pathway. We found: (1) HIIT could reduce HFD-induced body weight gain, liver fat and VAT mass in both OP/OR rats, and the influence in OP rats was even stronger. (2) After training, VAT of OP rats was more sensitive to catecholamine and showed stronger lipolysis compared with OR rats. (3) Increased β3-AR expression, rather than increased SNS activity, plays a key role in mediating these adaptive changes.

HIIT had a stronger influence on body weight, VAT mass, blood and liver lipids in OP compared with OR rats

Similarly to the heterogeneity of human obesity, rodents also show two different obesity phenotypes, namely OP and OR [14, 15]. Although the baseline weights of these rats are the same, marked differences in food intake, PA, central regulation and peripheral tissue metabolism lead OP rats to become obese after several weeks of receiving an HFD, while OR rats tend to remain at a normal weight [32,33,34]. We established a model of OP and OR rats by using a classic programme involving an HFD [14, 15, 34]. While establishing the model, the food intake and weight gain of OP rats were significantly higher than for OR rats, indicating that the model was established successfully.

Studies have shown that when the environment changes, OR individuals often exhibit a steady state of energy metabolism, while OP individuals respond more strongly to caloric restriction or food surplus [35, 36], suggesting that the OP phenotype has a survival advantage when energy is insufficient but is harmful during periods of excess food. Previous comparative studies of OP and OR have often focussed on aerobic exercise [20,21,22, 35, 36]. However, differently from aerobic exercise, HIIT consumes glycogen but not fat during exercise. There is an observation that many effective treatments (intermittent fasting, caloric restriction, pharmacological treatments, etc.) for metabolic syndrome have in common the ability to decrease liver and muscle glycogen and increase ketone bodies [37, 38]. Theoretically, HIIT has a similar glycogen-depleting effect, and OP phenotype generally shows faster fat synthesis/decomposition alternations. After HIIT, more intense lipolysis may occur in VAT of OP individuals, which could meet liver fatty acid and glycerol demands for ketogenisis and gluconeogenesis. However, whether HIIT could reduce VAT in OP phenotype more efficiently requires new evidence.

To our knowledge, this study compared the fat-loss effects of HIIT on OP and OR subjects for the first time. We found that HIIT had a stronger effect on reducing VAT in OP than OR rats, indicating that the differential adaptation of OP and OR subjects may be the reason for the strong heterogeneity of the HIIT fat-loss effect. Because the 12 weeks of training had no effect on the food intake, the heterogeneity of the VAT decrease between OP and OR rats may be more related to altered peripheral metabolism than feeding regulation by the central nervous system. The VAT mass in adulthood is more related to the volume rather than the number of adipocytes, and the main contributor (> 95%) of the cell volume comes from TG accumulation in lipid droplets [39, 40]. We found that after 6 weeks of an HFD, the adipocyte areas of OP rats were larger than that of OR rats, a finding that is characteristic of the classic OP animal model [41, 42]. After 12 weeks of HIIT, the cell area had decreased in both OP and OR rats, although the reduction was greater in OP rats, accompanied by an increase in the number of mitochondria (mean higher local lipid oxidation), suggesting that HIIT reduces the TG content of VAT in OP rats more strongly than OR.

Central obesity is a key component of metabolic syndrome. Excessive VAT accumulation is associated with hyperlipidaemia and non-alcoholic fatty liver disease (NAFLD) [43]. Exercise-induced decreases in VAT are often accompanied by decreased blood and liver lipids [44]. Our results are consistent with previous findings: the decreases of serum TG and liver lipids in OP rats were larger than in OR rats, indicating greater health benefits in the former group.

Generally, adipocytes of OP phenotype are more likely to enhance fat uptake after overfeeding [36]. Excessive VAT accumulation in could cause hypoxia, inflammation and IR, and these state will induce HSL activation and lipid overflow through the portal vein to liver and muscle (hyperlipidaemia and ectopic fat deposition) [38], greatly increasing the risk of NAFLD. As described above, HIIT may cause the exhaustion of glycogen and non-pathological ketogenesis, which have been shown to improve obesity and dysfunctional glucose/lipid metabolism [24]. After each session of HIIT, the adaptive dynamic rising of lipolysis in VAT may emerge for ketogenesis and gluconeogenesis in liver. This process is different from ‘uncontrolled’ lipolysis and lipid overflow and could be a healthy adaptation. In summary, HIIT showed a greater influence on the VAT mass, cell volume, hyperlipidaemia and liver lipid deposition of OP compared with OR rats, findings that imply a stronger catabolic change in adipose tissue of OP individuals.

VAT of OP rats showed greater lipolytic potential than OR rats after HIIT

Based on the data that the VAT of OP rats decreased more than OR rats after training, we hypothesised that heterogeneity in VAT changes between OP and OR rats is related to the different adaptations of adipocyte lipolytic pathways. Lipolysis is the primary step of TG decomposition, which refers to the process by which TG are hydrolysed into glycerol and non-esterified fatty acids (NEFA, the released form of TG). This process is mainly regulated by AR in the SNS [45, 46]. The SNS releases NE and epinephrine through nerve endings and adrenal glands, which can activate second messenger pathway (involving G proteins and cAMP) through AR, ultimately leading to PKA-mediated phosphorylation of HSL and activation of lipolysis [47]. Catecholamine release is correlated with exercise intensity [48]. Aerobic exercise mediates moderate secretion, which enhances lipolysis through β-AR of adipocytes to meet fat consumption during exercise, while high-intensity exercise induces excessive secretion of catecholamine and inhibits lipolysis through a negative feedback mechanism involving α-AR [49, 50].

Because minimal fat is burned during exercise, it is generally believed that HIIT can reduce fat based on post-exercise TG consumption [23, 24, 51]. A commonly mentioned view is that HIIT could increase excess post-exercise oxygen consumption (EPOC), but there are still controversies among existing results [52]. Another reasonable hypothesis is that due to the intense load of HIIT, during the recovery period, adipose tissue would release more lipid for gluconeogenesis, ketogenesis or tissue healing [24], which suggests that HIIT promotes adaptive catabolism of adipose tissue. Studies have verified the increase in β-AR and lipolysis in adipocytes after long-term HIIT [26, 28], supporting the hypothesis of adaptive changes in SNS lipolytic pathway. As mentioned earlier, when facing catabolic stress, OP individuals are more likely to show adaptation (fat is lost easily), while OR individuals are more likely to maintain homeostasis [35, 36]. Therefore, a reasonable explanation for the greater decrease in VAT mass of OP rats than OR ones after HIIT is that the visceral adipocytes of the former group generate a stronger adaptation to HIIT. SNS lipolytic pathway of OP phenotype is easier to start-up in face of gluconeogenesis, ketogenesis, tissue healing or metabolic stress.

It should be noted that excessive accumulation of VAT could result in IR and inhibition of the insulin receptor-PI3K/Akt pathway in adipocytes, which can also cause ‘uncontrollable’ HSL phosphorylation and lipolysis activation. Unlike IR-induced lipolysis, the SNS lipolytic pathway is only activated when the lipid demand of other organs increases. This process could be a healthy adaptation that does not induce hyperlipidaemia and ectopic fat deposits [44, 53]. Therefore, we hypothesized that HIIT increased VAT lipolysis via a mechanism related to adaptive changes in SNS-AR pathway but not the insulin receptor pathway.

To verify this hypothesis, we evaluated the expression and phosphorylation of HSL as well as catecholamine-induced glycerol release (lipolysis marker) from adipocytes in vitro. We found that after 12 h of fasting (inducing catecholamine release), there was no difference in HSL expression between the groups, but the level of phosphorylated HSLser660 was higher in the exercise groups than in the control groups, indicating an activating effect of HIIT on VAT lipolysis. Our in vitro experiment confirmed higher rate of lipolysis in the H-OP group after catecholamine stimulation, suggesting that there was stronger catabolism in the OP rats. In summary, these results suggest greater adaptation of the lipolysis regulation pathway in OP compared with OR rats.

Increased β3-AR expression may play a key role in mediating adaptive change to HIIT

Although VAT lipolysis in the H-OP group showed stronger adaptations to HIIT, the upstream mechanisms that mediate these changes remained unknown. Adipose tissue is regulated extensively by the neuroendocrine network. Although the SNS plays a primary role [54], parasympathetic nerves, natriuretic peptides, glucocorticoids and parathyroid hormone are also involved in regulating lipolysis [55]. Even downstream of the SNS, catecholamine and AR are not the only ‘transmitter–receptor’ pathway. Recent studies have reported other transmitters, receptors or intermediary cells such as neuropeptide Y (NPY), G-protein coupled receptor 3 (GPR3) and adipose mesenchymal cells (MSCs) involved in the SNS-mediated regulation of adipose catabolism [56,57,58]. Due to the existence of many pathways, the role of the SNS and β3-AR needed to be further confirmed in this study.

Because the hypothalamus is the major regulator of energy homeostasis and directly controls the SNS and food intake [54, 59], we speculated that the hypothalamus of OP rats could adapt to HIIT, thereby changing the feeding behaviour and SNS-regulated adipose metabolism. Unexpectedly, similarly to the food intake, results of TH expression didn’t support that HIIT promote NE release of sympathetic nerves. Whether changes in activity of the hypothalamus and SNS were related to the reduction of VAT required more experiments to explore. However, β3-AR expression of the exercise groups was increased significantly, and the increase was greater in the H-OP compared with the H-OR group, indicating that HIIT could increase more strongly the receptor number and the exercise adaptation of OP rats. To determine whether higher β3-AR expression produced stronger sensitivity to catecholamine, isolated adipocytes were stimulated by an ISO gradient (0.1–10 μM, to imitate levels of catabolism pressure) in vitro. The glycerol release of the H-OP group was significantly higher than the H-OR group, suggesting that adipocytes of OP rats are more sensitive to catecholamine and could produce more NEFA to export or local oxidation under the same SNS signal.

So far, three beta isoforms of AR have been reported (β1–β3). Although β3-AR predominates in white adipose tissue [60], studies have confirmed that gene polymorphisms of all three isoforms could affect the fat catabolism induced by aerobic exercise [61,62,63], although the relationship between HIIT and different isoforms had been unclear. To determine whether the VAT adaptation to HIIT is only related to β3-AR or also to other isoforms, we blocked this receptor with SR59230a, a selective antagonist, concomitantly with 10 μM ISO stimulation. Without the participation of β3-AR, the increased glycerol release in the H-OP group disappeared. These data confirm that increased expression of β3-AR, rather than β1-AR or β2-AR, plays a key role in increasing the sensitivity of adipocytes to catecholamine. In summary, after 12 weeks of HIIT, greater β3-AR expression in OP rats led to an elevated sensitivity to catecholamine compared with the OR rats. This change underlies the greater VAT lipolysis capabilities of OP rats.

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