Omar M. E. Abdel-Salam (ed.)Progress in Drug ResearchCapsaicin as a Therapeutic Molecule201410.1007/978-3-0348-0828-6_7
© Springer Basel 2014
7. Capsaicin as an Anti-Obesity Drug
(1)
111G, Division of Gastroenterology, Sepulveda Ambulatory Care Center, VAGLAHS, 16111 Plummer Street, Sepulveda, CA 91343, USA
(2)
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
(3)
VA Sepulveda Ambulatory Care Center, VAGLAHS, North Hills, CA, USA
Abstract
Laboratory studies support a role of capsaicin as an anti-obesity agent. Intestinal mucosal afferent nerves appear to play a role in controlling adipose tissue distribution between visceral and subcutaneous sites. Activation of the transient receptor potential vanilloid-1 channels by capsaicin prevents adipogenesis. A neurogenic mechanism modulates the regulation of fat metabolism by transient receptor potential vanilloid-1-sensitive sensory nerves. A neural pathway enables the selective activation of the central network that regulates brown adipose tissue sympathetic nerve activity in response to a specific stimulation of gastrointestinal transient receptor potential channels. Dietary capsaicin reduces metabolic dysregulation in obese/diabetic mice by enhancing expression of adiponectin and its receptor. The effects of capsaicin in adipose tissue and liver are related to its dual action on peroxisome proliferator-activated receptor alpha and transient receptor potential vanilloid-1 expression/activation. Local desensitization of the abdominal capsaicin-sensitive fibers attenuates the hypometabolic adaptation to food deprivation. Truncal vagotomy leads to significant reductions in both diet-induced weight gain and visceral abdominal fat deposition. Vagal de-afferentation leads to a more modest, but clinically and statistically significant, reduction in visceral abdominal fat. Thermogenesis and lipid metabolism-related proteins are altered upon capsaicin treatment in white adipose tissue. Capsaicin induces apoptosis and inhibits adipogenesis in preadipocytes and adipocytes. Epidemiologic data show that consumption of foods containing capsaicin is associated with a lower prevalence of obesity. Clinical evidence supports a role of capsaicin as an anti-obesity agent. Both oral and gastrointestinal exposure to capsaicin increase satiety and reduce energy and fat intake; the stronger reduction with oral exposure suggests a sensory effect of capsaicin. Bioactive components containing capsaicin may support weight maintenance after a hypocaloric diet. Capsaicin consumption 1 h before low intensity exercise is a valuable supplement for the treatment of individuals with hyperlipidemia and/or obesity because it improves lipolysis. Capsinoid ingestion increases energy expenditure through the activation of brown adipose tissue in humans. Capsinoid ingestion is associated with an increase in fat oxidation that is nearly significant; and two common genetic variants may be predictors of response. Further clinical research to develop convenient approaches for obese individuals to take advantage of this common dietary ingredient to prevent the onset or curtail the progression of obesity will be instructive and clinically relevant.
Disclosure: The author has no conflict of interest to declare.
7.1 Introduction
Laboratory and clinical studies support a role of capsaicin as an anti-obesity agent. This chapter reviews recent developments in this field. Systemic treatment with capsaicin, the active ingredient of hot pepper, or its analog is an accepted experimental method to induce functional ablation of the capsaicin-sensitive afferent nerves (Holzer 1991). Such functional impairment retarded body weight gain (Leung et al. 2007) and reduced total body fat (Melnyk and Himms-Hagen 1995) in rats. The capsaicin (vanilloid) receptor agonist (resiniferatoxin) (Gram et al. 2005; Moesgaard et al. 2005) reduced body fat and body weight and improved glucose tolerance in obese rats (Gram et al. 2005; Moesgaard et al. 2005). In experimental studies, when oral capsaicin was provided to rodents as 0.014 % of the diet (Kawada et al. 1986; Ohnuki et al. 2001), a dose equivalent to that ingested by rural Thai people (Interdepartment Committee on Nutrition for National Defense 1962), there was a significant 24 % (Kawada et al. 1986) and 29 % (Ohnuki et al. 2001) reduction in the weight of visceral (peri-renal) fat, but no effect on total caloric intake. These studies suggested the possibility that oral capsaicin treatment might regulate visceral adipose tissue metabolism.
Capsaicin absorbed from the gut lumen was almost completely metabolized before reaching the general circulation (Donnerer et al. 1990). A direct effect (Do et al. 2004; Hsu and Yen 2007a; Kang et al. 2003; Zhang et al. 2007) of oral capsaicin on adipose tissue at remote sites was unlikely. In support of this was also the fact that repeated administration of oral capsaicin (Leung et al. 2007) functionally desensitized the intestinal mucosal but not the corneal afferent nerves. The wiping reflex of the front paw of the eye exposed briefly to dilute capsaicin irritation was preserved in these rats treated with oral capsaicin for 14 days. Thus, if oral capsaicin could regulate adipose tissue distribution, the process might involve the intestinal mucosal afferent nerves.
The development of visceral obesity may be the result of the normal pattern of postprandial blood flow distributing absorbed fat nutrients preferentially to the adipose tissue at visceral sites. Ingested fat must pass through the intestinal lumen to be digested prior to absorption and distribution to various adipose tissue sites. Fat stored at any site must be delivered there by the systemic circulation. The intestinal mucosa is well-endowed with afferent nerve terminals (sensors), which mediate postprandial changes in intestinal and visceral adipose tissue blood flow. Their usual function may play a role in the accumulation of fat at visceral sites and impairment of their usual function may result in the accumulation of adipose tissue in nonvisceral sites. The results of a series of experiments (Leung et al. 2007; Leung et al. 2001; Leung et al. 2008) summarized in one review (Leung 2008) showed that attenuation of intestinal mucosal afferent nerve function may be a plausible approach to the treatment of visceral obesity. Stimulation of the intestinal mucosal capsaicin-sensitive afferent nerves by capsaicin produced a significant vasoconstriction in adipose tissue (Leung et al. 2001). Functional ablation of the intestinal mucosal capsaicin-sensitive afferent nerves led to loss of this vasoconstriction in the visceral but not subcutaneous adipose tissue (Leung et al. 2007). Further studies showed that the intestinal mucosal capsaicin-sensitive afferent nerves elicit events mediated by angiotensin II in adipose tissue (vasoconstriction) when nutrients were present in the intestinal lumen. When the intestinal mucosal capsaicin-sensitive afferent nerves were functionally ablated by repeated intragastric capsaicin treatment (Leung et al. 2007), the angiotensin II-mediated events were abolished in the visceral, but partially retained in the subcutaneous adipose tissue. The net effect was an angiotensin II-mediated and blood flow (vasoconstriction)-dependent distribution of absorbed fat nutrient(s) preferentially to the subcutaneous rather than the visceral adipose tissue. These studies provide the evidence to implicate the intestinal mucosal afferent nerves in the regulation of adipose tissue distribution.
7.2 Laboratory Studies
Long-term feeding experiments were undertaken in wild-type mice and transient receptor potential channel vanilloid type 1 (TRPV1) knockout mice. Compared with lean counterparts, in the visceral adipose tissue from obese db/db and ob/ob mice, and from obese human male subjects, there was a reduced expression of TRVP1. The oral administration of capsaicin for 120 days prevented the development of obesity in male wild-type mice but not in TRPV1 knockout mice assigned to high-fat diet. This activation of TRPV1 channels by capsaicin prevented adipogenesis and obesity (Zhang et al. 2007).
On a 4.5 % fat diet, wild-type and TRPV1-null mice gained equivalent body mass. On a 11 % fat diet, however, TRPV1-null mice gained significantly less mass and adiposity; at 44 weeks the mean body weights of wild-type and TRPV1-null mice were approximately 51 and 34 gm, respectively. Both groups of mice consumed equivalent energy and absorbed similar amounts of lipids. TRPV1-null mice, however, exhibited a significantly greater thermogenic capacity. Furthermore, 3T3-L1 preadipocytes expressed functional calcitonin gene-related peptide receptors. A potential neurogenic mechanism by which TRPV1-sensitive sensory nerves may regulate energy and fat metabolism (Motter and Ahern 2008).
Intragastric administration of capsiate resulted in a time- and dose-dependent increase in integrated brown adipose tissue sympathetic nerve activity over 180 min. This increase in brown adipose tissue sympathetic nerve activity was abolished by blockade of TRP channels as well as of sympathetic ganglionic transmission and was inhibited by ablation of the gastrointestinal vagus nerve. The activation of sympathetic nerve activity was delimited to brown adipose tissue and did not occur in the heart or pancreas. A neural pathway enables the selective activation of the central network regulating the brown adipose tissue sympathetic nerve activity in response to a specific stimulation of gastrointestinal TRP channels (Ono et al. 2011).
Based on the premise that metabolic dysregulation (hyperglycemia, hyperinsulinemia, hyperlipidemia) is a hallmark of obesity-related diseases such as insulin resistance, type 2 diabetes, and fatty liver disease, investigators assessed whether dietary capsaicin attenuated the metabolic dysregulation in genetically obese diabetic KKAy mice, which have severe diabetic phenotypes. Male KKAy mice fed a high-fat diet for 2 weeks received a 0.015 % capsaicin supplement for a further 3 weeks and were compared with nonsupplemented controls. Dietary capsaicin markedly decreased fasting glucose/insulin and triglyceride levels in the plasma and/or liver, as well as expression of inflammatory adipocytokine genes (e.g., monocyte chemoattractant protein-1 and interleukin-6) and macrophage infiltration. Expression of the adiponectin gene/protein and its receptor, AdipoR2, increased in adipose tissue and/or plasma, was accompanied by increased activation of hepatic adenosine monophosphate (AMP)-activated protein kinase, a marker of fatty acid oxidation. Dietary capsaicin reduces metabolic dysregulation in obese/diabetic KKAy mice by enhancing expression of adiponectin and its receptor (Kang et al. 2011).
Whether dietary capsaicin can reduce obesity-induced inflammation and metabolic disorders such as insulin resistance and hepatic steatosis was assessed in male C57BL/6 obese mice fed a high-fat diet for 10 weeks. They received a supplement of 0.015 % capsaicin for a further 10 weeks and were compared with unsupplemented controls. Dietary capsaicin lowered fasting glucose, insulin, leptin levels, and markedly reduced the impairment of glucose tolerance in obese mice. Levels of tumor necrosis factor-alpha (TNFα), monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-6 mRNAs and proteins in adipose tissue and liver decreased markedly, as did macrophage infiltration, hepatic triglycerides, and TRPV-1 expression in adipose tissue. The messenger ribonucleic acid/protein of adiponectin in the adipose tissue and peroxisome proliferator-activated receptor alpha/peroxisome proliferator-activated receptor-γ coactivator 1 alpha messenger ribonucleic acid in the liver increased. Luciferase assays revealed that capsaicin is capable of binding peroxisome proliferator-activated receptor alpha. Dietary capsaicin may reduce obesity-induced glucose intolerance by not only suppressing inflammatory responses but also enhancing fatty acid oxidation in adipose tissue and/or liver, both of which are important peripheral tissues affecting insulin resistance. The effects of capsaicin in adipose tissue and liver are related to its dual action on peroxisome proliferator-activated receptor alpha and TRPV-1 expression/activation (Kang et al. 2010).
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