The relationship between leptin and periodontitis: a literature review

The relationship between serum leptin levels and periodontitis

There is a complex bidirectional relationship between serum leptin levels and periodontitis.

Elevated serum leptin levels can exacerbate periodontitis. Han et al. (2022) discovered a worsened ligature-induced periodontitis after injecting leptin into the abdominal cavities of mice. Furthermore, high serum leptin levels activate nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes, promoting M1 macrophage polarization in a normal body. Activated M1 macrophages can subsequently secrete high amounts of inflammatory cytokines. Additionally, activated NLRP3 inflammasomes can promote the secretion of IL-1β and IL-18 by bone marrow-derived DCs in mice (Landman et al., 2003). High serum leptin levels can also downregulate the anti-inflammatory cytokine IL-37 (Yu et al., 2019). This chain of inflammatory reactions caused by elevated leptin levels further promotes periodontitis development.

Low serum leptin levels can also impact periodontitis. Lean defective mice, or ob/ob mice, are a mouse model with homozygous mutations in the leptin gene. They cannot produce leptin but still have intact leptin signaling pathways, which enables them to respond to exogenous leptin. Li et al. (2023) recently observed the periodontal tissue status and alveolar bone phenotype of ob/ob mice. According to the results, ob/ob mice exhibited higher levels of inflammatory markers and osteoclast markers in periodontal tissue, more distance between the enamel-cementum junction and the alveolar crest, and more severe alveolar bone loss than wild-type mice (Li et al., 2023). Additionally, Hoffmann et al. (2019) confirmed that the physiological leptin levels (0.1–3.0 mg/kg) can significantly reduce the circulating inflammatory cytokine levels when injected intraperitoneally in ob/ob mice. Low serum leptin levels may thus be a risk factor for periodontitis, whereas low-dose exogenous leptin injections can reduce proinflammatory cytokine levels and promote bone formation.

Periodontitis can also increase serum leptin levels. Serum leptin levels in patients with periodontitis were positively correlated with periodontal clinical parameters in various clinical trials (Gualillo et al., 2000; Karpavicius et al., 2012; Lee & Bae, 2016). However, a recent clinical comparative study demonstrated that patients with periodontitis in high-altitude areas had lower serum leptin levels than a group of 50 healthy controls and that the serum leptin levels were negatively correlated with probing depth and clinical attachment loss (Yan et al., 2022). The inverse relationship observed between serum leptin levels and periodontitis in this study may be attributed to the specific sample selection and sample size. The divergent results in the studies discussed earlier suggest that various factors could contribute to alterations in serum leptin levels during the progression of periodontitis. It also highlights that the relationship between periodontitis and serum leptin levels needs further clarification and to be explained by additional relevant molecular mechanisms.

Obesity

Obesity is excessive fat accumulation in specific body parts, increasing body weight. Obesity and periodontitis have been positively linked in various studies and analyses of systematic diseases. Obesity and periodontitis have a comorbidity relationship, primarily characterized by shared inflammatory pathways, and they can both cause immune dysregulation (Ganesan, Vazana & Stuhr, 2021; Jepsen, Suvan & Deschner, 2020).

Adipose tissue is the main source of leptin, and obese individuals secrete more leptin than healthy people. The elevated leptin levels in obese individuals could promote inflammatory cytokine activation in the body, disrupting the oral microbiota and exacerbating periodontitis development (Chaves et al., 2022; Toy et al., 2023). Furthermore, the obesity-related increase in serum leptin levels lowers the cortical bone density in the alveolar bone area, exacerbating alveolar bone loss. Periodontitis can also affect obesity by influencing leptin. Li et al. (2015) discovered that periodontitis could upregulate both leptin and its receptor levels, thus increasing proinflammatory cytokine (IL-6 and IL-8) expression in periodontal ligament cells. Therefore, general periodontitis patients have high levels of various inflammatory mediators (IL-1β, TNF-α, IL-6, and so on) in their periodontal tissues (Bullon et al., 2009; Shimada et al., 2010). These increased inflammatory mediators could establish a connection between the inflamed periodontal tissues and the rest of the body through the bloodstream. The above-mentioned inflammatory factors can also promote adipose tissue lipolysis, increase liver fat synthesis and lipidation, block hepatic glucose metabolism, and aggravate lipid metabolism disorders (Fentoglu & Bozkurt, 2008; Saito et al., 2008). Based on the above findings, it is apparent that obesity can promote the progression of periodontitis by upregulating serum leptin levels, while periodontitis can impact the extent of obesity by influencing leptin.

Furthermore, investigating the shifts in the microbial environment in ob/ob obese mice adds a crucial dimension to understanding the link between obesity and periodontitis. On one hand, the absence of leptin can bring about alterations in the gut microbiota. As demonstrated in Ley et al. (2005), ob/ob mice exhibit a significant reduction in Bacteroidetes and a corresponding increase in Firmicutes in their gut composition. This shift may potentially contribute to the onset of obesity (Ley et al., 2005), which in turn can exacerbate the progression of periodontitis. On the other hand, leptin deficiency also leads to transformations in oral microorganisms. In comparison to the wild-type, ob/ob mice demonstrate reduced abundance of two beneficial bacteria, Akkermansia and Ruminococcaceae UCG 014, that naturally exist in the oral cavity. Additionally, there is an increase in the presence of inflammatory bacteria (Li et al., 2023). This suggests that dysbiosis in the oral microbiota significantly contributes to alveolar bone loss in leptin-deficient obese mice.

Diabetes

Type 2 diabetes (T2D) can exacerbate periodontitis by influencing leptin. In a past study, serum leptin levels were significantly higher in diabetic patients than in the control group (Lai et al., 2020). Elevated serum leptin levels can enhance the body’s inflammatory response and exacerbate periodontitis. Moreover, T2D-induced hyperleptinemia can exacerbate periodontitis via aggravating extracellular matrix (ECM) degradation in gingival fibroblasts (Williams et al., 2016).

Conversely, periodontitis can impact diabetes by influencing leptin. Periodontitis can upregulate serum leptin levels and, through the JAK2/STAT3 signaling pathway, regulate the involvement of the suppressor of cytokine signaling (SOCS) in cytokine signaling transduction inhibition, which affects T2D incidence (Zhang et al., 2022). Moreover, elevated TNF-α in serum worsened diabetes by stimulating C-reactive protein leading to increased insulin resistance and glucose levels (Anton et al., 2020; Santos Tunes, Foss-Freitas & Nogueira-Filho, 2010). Leptin can also secrete TNF-α by activating blood monocytes (Constantin & Costache, 2010). High serum leptin levels in periodontitis suggest elevated severity of insulin resistance.

Cardiovascular diseases

Serum leptin levels have been shown to be associated with cardiovascular disease. Elevated leptin levels, above 10 ng/L, have been linked to a notable increase in the risk of cardiovascular disease (Selvarajan et al., 2015). Moreover, a high concentration of serum leptin can independently serve as a predictive factor for mortality in stroke patients with coronary heart disease (Puurunen et al., 2017). Research indicates that leptin plays a role as one of the mediators in the development of atherosclerosis. It has the direct capability to stimulate the recruitment of monocytes to the arterial intima and induce the production of pro-inflammatory cytokines (Liberale et al., 2017; Scheja & Heeren, 2019), thereby triggering the onset of cardiovascular diseases.

Of note, periodontitis increases the serum leptin levels (Zhu et al., 2017), may due to the altered oral microbiome disorder in patients with periodontitis. In patients with periodontitis, the presence of oral Porphyromonas gingivalis is significantly higher compared to those without the condition (Noack et al., 2001). This bacterium’s cell wall product, lipopolysaccharide (LPS), triggers an excessive release of inflammatory factors like TNF-α, IL-6, IL-8, and IL-1β in the oral cavity through the innate immune response, subsequently entering the systemic circulation (Santos Tunes, Foss-Freitas & Nogueira-Filho, 2010). Finck’s research demonstrated a significant elevation in plasma leptin levels following the intraperitoneal injection of recombinant TNF-α in rats. This indicates that TNF-α induces leptin production via the p55 TNF receptor (Finck & Johnson, 2000). This implies that the substantial secretion of inflammatory factors in the mouths of periodontitis patients can potentially impact systemic circulation, thus heightening serum leptin levels, posing a threat to cardiovascular health. Furthermore, it should be noted that Porphyromonas gingivalis not only indirectly influences leptin levels, posing a threat to cardiovascular health, but the outer membrane vesicles it generates can be released into the environment, promoting the calcification of vascular smooth muscle cells. This calcification is a significant hallmark of atherosclerosis (Zhang et al., 2021).

Based on the above discussion, it is apparent that serum leptin levels, systemic diseases, and periodontitis all have a complex and bi-directional relationship. Leptin may be involved in periodontitis development, whereas periodontitis may affect the pathological process of systemic diseases by influencing leptin. In other words, leptin, to a certain extent, acts as a bridge connecting local tissue inflammation in periodontitis and systemic diseases. Therefore, the dual effects of leptin should be fully considered when treating periodontitis and associated diseases. Oral microbial imbalance can influence both periodontitis and systemic health issues via the leptin pathway. Consequently, future research endeavors might emphasize efforts to prevent or restore a balanced oral ecology. This could be achieved through lifestyle modifications or the development of innovative therapies like prebiotics and probiotics (Păunică et al., 2023). In addition, a critical focus for upcoming research should involve delving deeper into the systemic regulatory mechanism of leptin and elucidating its association with systemic diseases (Obradovic et al., 2021).

The effects of leptin on local bone metabolism in periodontal tissue

For adultsthe progression of periodontitis is influenced by the degree of alveolar bone resorption, which is the primary cause of tooth loss (Sanz et al., 2020). By acting on the nervous system, leptin regulates local bone metabolism in the periodontal tissue, and it can also directly influence the metabolic state of the alveolar bone.

On the one hand, by acting on the central nervous system (CNS), leptin can indirectly participate in local bone metabolism in the periodontal tissue. Recent research has revealed how leptin influences bone metabolism via the CNS. After binding to its receptors on glucose-sensitive neurons in the hypothalamus, leptin activates the adrenal receptor beta 2 (Adrb2) in osteoblasts, downregulates c-myc gene expression, and increases cyclin D production, ultimately lowering osteoblast proliferation. Furthermore, Adrb2 activation promotes the receptor activator of nuclear factorκB ligand (RANKL) expression via the protein kinase A and activating transcription factor four pathways, thereby enhancing the function of osteoclasts bone resorption (Chen & Yang, 2015; Reid, Baldock & Cornish, 2018).

On the other hand, leptin can directly act on the periodontal tissue to regulate bone metabolic processes. Both the human periodontal membrane cells and primary cultured human dental pulp cells have high mineralization ability and certain osteoblast-like characteristics (Sun et al., 2018). Leptin has been shown to promote human periodontal membrane cell proliferation, implying that it can promote osteogenesis by influencing osteoblast-like cell proliferation. Following leptin stimulation, the mineralization percentage of bone-forming cells in the periodontal tissue increases, and RANKL mRNA expression decreases, indicating that leptin promotes osteogenesis. Human periodontal membranes are primarily comprised of fibroblasts. When stimulated with leptin in vitro, the ratio of osteoprotegerin (OPG) to RANKL in human gingival fibroblasts (HGFs) changes significantly. The OPG/RANKL ratio increases under low-concentration leptin stimulation exerting a bone-protective effect and reducing osteoclast production, but decreases under high-concentration stimulation (Guo et al., 2021). This suggests that varying concentrations of leptin have distinct effects on bone metabolism within the periodontal tissue. Studies have demonstrated that human growth arrest-specific protein 6 (GAS6) is expressed in oral mucosal epithelial cells and stimulate periodontal membrane cell osteogenesis (Zhang et al., 2020). In contrast, leptin can reduce the GAS6 levels when stimulating periodontal membrane cells (Yong et al., 2023).

In addition to the above-mentioned findings, leptin may promote bone resorption by impacting the expression levels of certain inflammatory factors, including TNF and IL-6, which participate in the activation the function of osteoclast bone resorption (Faienza et al., 2019; Wang & He, 2018).

Overall, leptin is closely related to alveolar bone metabolism and can influence it in multiple ways. Their relationship is complex, encompassing several signaling pathways, and to fully understand the underlying mechanism, a comprehensive assessment of the interaction is necessary.