Despite evidence that the ability to taste is weakened by obesity and can be rescued with weight loss intervention, few studies have investigated the molecular effects of obesity on the taste system. Taste bud cells undergo continual turnover even in adulthood, exhibiting an average life span of only a few weeks, tightly controlled by a balance of proliferation and cell death. Recent data reveal that an acute inflammation event can alter this balance. We demonstrate that chronic low-grade inflammation brought on by obesity reduces the number of taste buds in gustatory tissues of mice—and is likely the cause of taste dysfunction seen in obese populations—by upsetting this balance of renewal and cell death.

Taste buds operate not only as sensors of essential nutrients but can also trigger powerful central reward from the consumption of hedonically pleasing food. Obese individuals have been reported to display a weakened sense of taste and thus may be driven to consume more calories to attain such reward. Here, we have analyzed the effects of obesity on taste buds and demonstrate that mice consuming a high-fat diet quickly become obese and display a pronounced loss of taste buds when compared to littermates sustained on a healthy diet. When the inflammatory response is impeded via genetic manipulation, we observe that mice no longer suffer taste loss, suggesting that taste dysfunction in obesity is a result of systemic inflammation. We also find that obesity-resistant mice consuming the same unhealthy diet have no change in the taste bud abundance, confirming that taste loss is a metabolic consequence of the obese state rather than a response to oral exposure to fat. Our results validate a role for taste in the genesis of obesity and suggest a novel direction in the treatment of obesity.

Introduction

Obesity is one of the world’s most prevalent public health issues, affecting over one-third of United States citizens [1] and is associated with increased mortality, along with various comorbidities, including cardiovascular disease, diabetes, stroke, and cancer [2]. The treatment of obesity presents major challenges, including poor adherence to diets, with high rates of attrition [3]. Despite many studies outlining the effects of obesity, people continue to eat unhealthy diets. Various studies have investigated the relationship between body mass index (BMI) and taste perception with differing results. Earlier reports suggest little to no effect of BMI on taste sensitivity [4,5]. These studies tested detection thresholds for sweet stimuli in obese and normal-weight humans but failed to take into account individual variation in the perception of suprathreshold stimuli. With the invention of the generalized Labeled Magnitude Scale (gLMS), intensity ratings could be compared better across groups by anchoring the upper end of intensity scales to the “strongest imaginable sensation of any kind,” rather than strongest taste sensation, thus negating bias from the obese fundamentally perceiving taste differently [6]. Use of the gLMS revealed a negative association between BMI and perceived intensity of sweetness, umami, saltiness, and fatty taste [7–10]. This relationship, however, remains complex and methodology dependent, with not all studies in agreement and some studies finding an opposing relationship to be true [11]. Researchers have also explored the association between high BMI and decreased dopamine signaling from food intake, suggesting that the obese and overweight seek out more palatable foods to compensate for depressed reward [12,13]. Weight loss interventions, both gradual and acute (i.e., via bariatric surgery), have also proven to alleviate obesity-related alterations in taste function, suggesting a bidirectional relationship between adiposity and taste. Gastric bypass surgery in both rodents and humans can reestablish taste thresholds and reward signaling to levels seen in normal-weight controls, as well as decrease the preference for, and intake of, calorie-rich foods [14–21]. Despite evidence that taste is weakened in obesity, and rescued with weight loss intervention, few studies have investigated the molecular effects of obesity on the taste system. Despite this, various groups studying functional responses from taste buds of obese rodents have noted an altered response to sweet and fat stimuli [22–24], often accompanied by a decreased behavioral response.

A taste bud consists of a heterogeneous collection of 50 to 100 cells belonging to three functionally independent cell types. Type I cells are considered glial-like, provide structural support for the taste bud, and are likely responsible for salty taste detection [25]. Type II cells express G-protein–coupled receptors (GPCRs) for sweet, bitter, or umami tastants and transduce taste signals via the phospholipase C beta 2 (PLCβ2)/phosphatidylinositol bisphosphate (PIP2)/inositol triphosphate (IP3) cascade [26–28]. Type III cells form synapses with afferent nerve fibers and respond to sour taste [29,30]. Type II cells release ATP as their primary neurotransmitter [31,32], while Type III cells accumulate and release serotonin and synthesize the inhibitory transmitter gamma aminobutyric acid (GABA) [33]. Taste bud cells undergo continual turnover, even into adulthood, exhibiting an average life span of about 10 days [34]. Recently, a population of lingual stem cells has been identified that give rise to mature taste bud cells in the circumvallate papillae [35]. These cells express the leucine-rich repeat-containing G-protein–coupled receptor 5 (LGR5), which is also expressed by stem cells of the intestinal epithelium. LGR5 has been identified as a receptor for R-spondins, which activate the Wnt signaling pathway [35,36]. Upon activation of Wnt, these LGR5-expressing stem cells differentiate into immature sex-determining region Y box 2 (SOX2+) cells and migrate into the taste bud, losing their LGR5 expression in the process. SOX2 is required for the differentiation of endodermal progenitor cells of the tongue into mature taste bud cells and represents one of the last steps before terminal differentiation [37].

There are a number of processes that affect the generation of new functional taste cells from immature progenitor cells. Acute lipopolysaccharide (LPS)-induced inflammation has been shown to inhibit proliferation of taste progenitor cells and reduce the number of newly born cells entering taste buds. Furthermore, LPS-induced inflammation was shown to moderately shorten the average lifespan of mature taste bud cells [38], alongside a notable immune response. These experiments show the effects of inflammation in short-term, acute administration, a relatively rare occurrence. More common in human populations is the chronic and systemic low-grade inflammation found in obesity, the effects of which are yet to be fully catalogued in taste. While an acute immune response fundamentally differs from the sterile low-grade immune activity observed with obesity, notable parallels still persist. Evidence indicates that a state of low-grade chronic inflammation has a crucial role in the pathogenesis of obesity-related metabolic dysfunction [39,40]. With increased amounts of visceral adipose tissue, the production of proinflammatory cytokines—including tumor necrosis factor α (TNFα), interleukin 6 (IL6), and C-C motif chemokine ligand 2 (CCL2)—is up-regulated in the obese, with the potential to act on receptors within the taste bud, inducing cell death cascades [41,42]. TNFα in particular has been well documented as a key mediator of obesity-related pathologies [39,40,43]. TNFα-null mice have notably superior insulin sensitivity when obese through diet, with lower free–fatty acid levels [44] and with triglycerides and leptin also reduced [45]. This study investigates the effects of low-grade inflammation on the regenerative processes of taste buds in the obese state, demonstrating a biological mechanism for taste dysfunction seen in human sensory studies of obese populations.