There are four major models that have been promoted to explain the beneficial effects of culinary capsaicin on weight gain. According to the first and oldest theory, capsaicin exacerbates intestinal passage and thereby reduces the absorption of calories ^[1][59]. This model is in keeping with the well-known ability of hot, spicy food to cause diarrhea in infants ^[2][60] and sensitive individuals ^[3][61]. The second theory posits that capsaicin can boost thermogenesis ^[4][5][62,63]. The third model connects capsaicin-sensitive visceral afferents to the arcuate nucleus ^[6][64], the center of appetite regulation. Finally, the fourth theory that has gained popularity recently assumes that capsaicin can change the gut microbiota in a way that may help maintain a healthy body weight ^[7][65]. Since the effect of capsaicin on gut bacteria is not mediated by TRPV1 (so in a way it is non-specific), it will be discussed below under a separate subheading.

The GI tract is densely innervated by capsaicin-sensitive (TRPV1-expressing) nerves that sense visceral pain (afferent function) and regulate intestinal motility (efferent function) ^[8][9][67,68]. In rats, dietary capsaicin stimulates mucus production in the colon that, in turn, may reduce fat absorption ^[10][12]. In men, capsaicin hastens the intestinal transit of the meal ^[11][12][69,70], although it has no effect on gastric emptying ^[13][71]. This is in accord with the reduced fat absorption that was noted in rats when capsaicin was added to the chow ^[14][10]. Furthermore, capsaicin can cause gastrointestinal distress that, in turn, may suppress the desire to eat more ^[15][16][37,72]. Somewhat unexpectedly, epithelial cells in the human gut were also shown to express functional TRPV1 ^[17][18][19][73,74,75], implying a direct capsaicin effect on the GI mucosa.

There is good evidence that capsaicin can boost thermogenesis, both shivering and non-shivering ^[4][5][62,63]. In experimental animals, capsaicin can induce hypothermia and initiate counter regulatory mechanisms, such as shivering, to generate heat ^[20][21][76,77]. In men, dietary capsaicin is known to induce “gustatory sweating” ^[22][78]. To explain the popularity of “hot” food under tropical climates, it was speculated that capsaicin can cool the body (capsaicin as “natural air conditioner”) ^[23][79].

Of note, visceral TRPV1-expressing afferents have been implicated in the thermoregulatory action of capsaicin ^[24][80]. Thus, the activation by capsaicin of the same afferents may reduce the calorie intake by speeding the intestinal transport of food, and, at the same time, increase energy expenditure by lowering the body temperature. Furthermore, these vagal afferents when stimulated by capsaicin may activate appetite-suppressant CART (cocaine, amphetamine, and proopiomelanocortin-regulated) neurons in the arcuate nucleus ^[25][81]. It should be noted here that CART neurons themselves express TRPV1, therefore, they may also be directly activated by capsaicin ^[26][82].

Brown adipose tissue (BAT) is a key player in non-shivering thermogenesis ^[27][28][83,84]. Indeed, there is an inverse relationship between BAT and obesity. Dietary capsaicin was reported to “brown” the white adipose tissue ^[4][29][30][62,85,86]. For example, near-infrared time-resolved spectroscopy (NITR) detected a 46% increase in brown adipose tissue in 20 volunteers on daily capsaicin for 8 weeks ^[31][87].

Both murine and human visceral adipose tissue seem to express TRPV1 ^[32][88]. In mice, capsaicin increased the phosphorylation of sirtuin-1 (SIRT-1) ^[33][89], a protein that is involved in lipid metabolism ^[34][90]. This effect was prevented by capsazepine, a TRPV1 antagonist ^[35][91], and was absent in TRPV1-null mice ^[33][89], indicating a TRPV1-mediated capsaicin action. Furthermore, capsaicin protected the expression of the thermogenic genes, ucp-1, bmp8b, pgc-1α, and prdm-16, from HFD-induced downregulation ^[33][89]. In a second study, TRPV1 activation elevated UCP-1 (uncoupling protein-1) protein content in the brown adipose tissue of the mouse and protected the animals from HFD-induced visceral fat accumulation ^[36][92]. Since UCP-1 is a known player in the “browning” of the white adipose tissue ^[37][93], this observation may provide a mechanistic explanation for fat “browning” by capsaicin ^[30][86].

This is interesting animal research, but is it relevant for dietary capsaicin actions in men? In other words, can dietary capsaicin reach human adipose tissue in concentrations that are high enough to replicate the effects that are seen in mice? Probably not. Although capsaicin is readily absorbed from the GI tract of both rats ^[38][94] and men ^[39][40][95,96], it is rapidly metabolized in the liver, producing 126 transformation products ^[41][42][97,98]. Although some of the capsaicin metabolites were detected in human urine ^[42][98], it is not known if any of these compounds may mimic capsaicin actions on adipose cells. In human volunteers, the half-life of capsaicin in the blood was approximately 25 min with a peak concentration of 8.2 nM ^[40][96]: this should be compared to the affinity of capsaicin for human TRPV1, 640 nM ^[43][99].

The effect of the gut microbiota on health and disease is subject to intense research. Gut bacteria play a critical role in colonic health ^[44][100]. What we eat will either help maintain a healthy microbiota in the colon, or cause disease by killing “good” bacteria and supporting the growth of pathogens. There is a growing body of evidence linking abnormal gut microbiota ^[45][101] and a malfunctioning gut-microbiota-brain axis ^[46][102] to obesity. Indeed, a transplant of fecal microbiota from adult twins discordant for obesity to germ-free mice recapitulated the phenotype (lean versus obese) of the fecal donor ^[47][103]. Importantly, the mice could be rescued from fecal transplant-induced weight gain by microbiota of the lean animals ^[47][103]. These findings reveal transmissible and modifiable effects of the gut microbiota on obesity.

Body fat content seems to correlate with gut microbiota diversity: the higher the fat, the lower the diversity ^[48][104]. For instance, obese people host more firmicutes and fewer Akkermansia in their GI tract ^[49][105]. Conversely, weight loss interventions increase the abundance of Akkermansia, an “antiobesity” bacterium, in the stool ^[50][106]. Many pre- and probiotics that are used to treat obesity were shown to restore the normal diversity of the gut microbiome ^[51][107]. Capsaicin may correct this “dysbacterosis” via multiple mechanisms as an alternative to “fecal transplant” ^[52][108].

In the C57BL/6J mouse, capsaicin (2 mg per os) was reported to increase the contribution of Akkermansia to the gut microbiota, presumably by stimulating mucin production in the colon ^[10][12]. In this context, it may be relevant that mucin-producing columnar epithelium in the colon expresses TRPV1 ^[53][109]. However, this capsaicin effect was seen both in the TRPV1-null and wild-type animals, indicating a non-specific (that is, not capsaicin receptor-mediated) action ^[52][108]. Capsaicin may also improve the bacterial diversity by eliminating pathogens directly ^[54][110].

Chronic low-grade inflammation has been implicated in the pathomechanism of obesity and metabolic syndrome ^[55][111]. The dysbacteriosis, in particular the overgrowth of the S24-7 bacterium family that occurs in the obese, can lead to metabolic endotoxemia, which, in turn, may maintain this low-grade inflammation ^[56][112]. Capsaicin may represent a novel dietary strategy to prevent endotoxemia ^[57][113]. Indeed, dietary capsaicin was reported to reduce the number of Gram-negative lipopolysaccharide (LPS)-producing bacteria in the stool ^[57][113]. Importantly, in this study the capsaicin-fed animals gained less weight when they were kept of HFD, and the protective effect of capsaicin was transferable to mice on a control diet by fecal transplant ^[57][113].

Last, LPS has been shown to both directly activate TRPV1 ^[58][114] and to indirectly sensitize capsaicin-sensitive afferents ^[59][115], creating a “microbe-gut-nerve-brain axis”. This loop may be disconnected capsaicin-desensitization.

In conclusion, dietary capsaicin may aid in restoring the “pro-lean” gut microbiota.

The topical application of 0.075% capsaicin cream to the skin of mice that were fed HFD significantly reduced weight gain and visceral fat ^[60][116]. Topical capsaicin also reduced serum glucose and triglyceride levels ^[60][116]. Furthermore, ovalbumin-allergic mice that were treated topically with a 0.075% capsaicin cream displayed attenuated food allergy symptoms (e.g., reduced blood eosinophilia and IgE levels), restoring normal appetite and body weight ^[61][117].

Topical capsaicin may be an attractive approach for people who either dislike “hot” spicy food or experience GI symptoms such as abdominal pain and bloating after eating it. However, this observation with low concentration (0.075%) capsaicin is difficult to apply to men since the analgesic capsaicin patch employs a 100-fold higher (8%) concentration.

Although topical capsaicin is readily absorbed from the human skin ^[62][118], its concentration in the blood probably stays low. Indeed, the horse-sensitive methods (e.g., UHPLC and MS) failed to detect any capsaicin in the blood after treating the skin of the animals with 0.1% capsaicin for 5 days ^[63][119]. Furthermore, dermal capsaicin evokes a blunted pain and flare response in the skin of obese individuals, indicative of reduced capsaicin sensitivity ^[64][120]. High-dose (8%) capsaicin patches are in clinical use to relieve chronic neuropathic pain ^[65][121]. As yet, no clinical study with dermal capsaicin creams or patches have been done to test any effect on body weight.

Capsaicin-sensitive neurons are bi-directional neurons with somata in sensory (dorsal root and trigeminal) ganglia ^[8][9][66][4,67,68]. The peripheral terminals of these neurons are sites of release for neuropeptides (for example, substance P, SP, and calcitonin gene-related peptide, CGRP) that initiate the biochemical cascade that is known as neurogenic inflammation ^[9][66][4,68]. The central efferents enter the spinal cord where they make synapse with second order neurons of the dorsal horn ^[9][66][4,68]. These efferents convey nociceptive information into the central nervous system. The role of these neurons in pain sensation, and the efforts to develop clinically useful analgesic agents that block the capsaicin receptor TRPV1, were detailed elsewhere ^[67][68][69][122,123,124]. Here it suffices to mention that the initial excitation by capsaicin of these neurons is followed by a lasting refractory state, traditionally termed “desensitization” ^[9][66][4,68]. Neonatal capsaicin administration can also kill these neurons ^[70][125]. As a tool to dissect the function of capsaicin-sensitive afferents, desensitization of adult animals seems to be preferable since rodents that grow up without such nerves due to neonatal treatment may develop compensatory mechanisms. Indeed, newborn rats whose TRPV1-expressing neurons had been eliminated by capsaicin (50 mg/kg s.c.) show no change in body weight as adults compared to solvent controls ^[71][126]. This is in sharp contrast to rats that were desensitized to capsaicin as adults: these animals stay lean because they resist aging-associated weight gain ^[72][127]. Gaining weight in the elderly has been linked to increasing circulating CGRP levels ^[73][128]. Capsaicin desensitization depletes CGRP ^[9][66][4,68], and thus may prevent the age-related increase in circulating CGRP.

With intraperitoneal capsaicin administration (5 mg/kg), the visceral vagal afferents can be selectively desensitized with no global effect on capsaicin-sensitive neurons. After this intervention, rats were deprived of food for 5 days. During these 5 days of food deprivation, the capsaicin-treated animals lost 18.9 g whereas the controls lost 15.8 g: that is, the capsaicin group showed 20% more weight loss ^[74][129].

Visceral fat is thought to be more deleterious than subcutaneous adipose tissue. Intact capsaicin-sensitive intestinal afferent function seems to be essential for the redistribution of fat from viscera to subcutis ^[75][130].