Olfaction and food intake are interrelated and regulated. In the process of feeding, the metabolic signals in the body and the feeding signals produced by food stimulation are first sensed by the arcuate nucleus of hypothalamus and the nucleus tractus solitarius of brain stem, and then these neurons project to the paraventricular nucleus of hypothalamus. The paraventricular nucleus transmits the signals to other brain regions related to feeding and regulates feeding behavior. In this process, olfactory signals can be transmitted to hypothalamus through olfactory bulb and olfactory cortex to regulate feeding behavior. At the same time, gastrointestinal hormones (ghrelin, insulin, leptin, etc.) and some neurotransmitters (acetylcholine, norepinephrine, serotonin, endocannabinoid, etc.) produced in the process of feeding act on the olfactory system to regulate olfactory function, which in turn affects the feeding itself. This review summaries the research progress of the interaction between olfaction and food intake and its internal mechanism from the aspects of neuronal and hormonal regulation.
Arcuate Nucleus of Hypothalamus/metabolism* ; Feeding Behavior/physiology* ; Hypothalamus ; Paraventricular Hypothalamic Nucleus ; Smell

The social problems and medical burdens caused by obesity have become more serious in recent years. Obesity is mainly caused by the imbalance of energy intake and consumption in the body. The central nervous system and related neurons regulate the balance of energy metabolism. The hypothalamic arcuate nucleus (ARC) contains anorexigenic proopiomelanocortin (POMC) neurons and orexigenic neuropeptid Y(NPY)/agouti-related protein (AgRP) neurons that regulate the feeding behavior of body. High-fat diet induces phosphorylation of Rb protein in POMC neurons, and inactivation of Rb phosphorylation leads to re-entry of POMC neurons from the resting-state into the cell cycle, which rapidly shifts to apoptosis. High-fat diet also causes the inhibition of neuronal regeneration, induces inflammation and neuronal damage, loss of neuronal homeostasis, leptin resistance, and ultimately leads to obesity. This review discusses the relationship between loss of neuronal homeostasis and dietary obesity, as well as the underlying mechanisms, which might provide the evidence for prevention and treatment of these diseases.
Arcuate Nucleus of Hypothalamus ; Homeostasis ; Humans ; Leptin ; Obesity ; Pro-Opiomelanocortin

Over the last 5 years, the Korean Ministry of Food and Drug Safety has approved four anti-obesity drugs for long-term weight management. In this review, the mechanisms of action and clinical applications of lorcaserin, naltrexone/bupropion, liraglutide, and phentermine/topiramate have been clarified. Lorcaserin stimulates proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons in the arcuate nucleus. Naltrexone/bupropion reduces body weight by controlling the hedonic reward system of food intake. The hypophagic effect of liraglutide depends on the direct activation of the proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons and indirect suppression of neuropeptide Y/agouti-related peptide neurons through gammaaminobutyric acid-dependent signaling, with an additional thermogenic effect. Phentermine/topiramate induces weight loss by elevating the norepinephrine levels in the hypothalamus, reducing energy deposition in the adipose tissue and skeletal muscle, and elevating the corticotropin-releasing hormone in the hypothalamus. In patients with high cardiovascular risks or type 2 diabetes mellitus, lorcaserin and liraglutide are appropriate. In patients with mood disorders, naltrexone/bupropion could be considered as the first choice of therapy. Notably, lorcaserin and liraglutide are neutral in the aspect of sleep disorder. In case of obese individuals with obstructive sleep apnea, liraglutide or phentermine/topiramate would be selected as the treatment option. These four drugs should be used after considering the patients' co-morbidities of obesity.
Adipose Tissue ; Anti-Obesity Agents ; Arcuate Nucleus of Hypothalamus ; Body Weight ; Corticotropin-Releasing Hormone ; Diabetes Mellitus, Type 2 ; Eating ; Humans ; Hypothalamus ; Korea ; Liraglutide ; Mood Disorders ; Muscle, Skeletal ; Neurons ; Neuropeptides ; Norepinephrine ; Obesity ; Pharmacology ; Reward ; Sleep Apnea, Obstructive ; Sleep Wake Disorders ; Weight Loss

Hydrogen sulfide (HS) contributes to visceral hyperalgesia in primary sensory neurons, but its role in central nervous system remains largely unknown. This study was to investigate the roles and underlying mechanisms of HS and its endogenous synthesis enzymes in the arcuate nucleus (ARC) in rat pancreatic hyperalgesia. Chronic pancreatitis (CP) was induced in male adult Sprague-Dawley rats by intra-pancreatic ductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. Western blot analysis was performed to detect protein expression in the ARC. CP markedly upregulated cystathionine β-synthetase (CBS) expression but did not alter cystathionine-γ-lyase level in the ARC at 4 weeks after TNBS injection. Although the expression of total GluN2B was not altered, CP greatly enhanced the phosphorylation level of GluN2B in the ARC when compared with age- and sex-matched control rats. CP also significantly increased expression of protein kinase Cγ (PKCγ) in the ARC. Arcuate microinjection of O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA, an inhibitor of CBS) significantly attenuated abdominal pain in CP rats in a dose-dependent manner and reversed the CP-induced upregulation of p-GluN2B and PKCγ in the ARC. Furthermore, the GluN2B inhibitor or specific PKC inhibitor chelerythrine significantly attenuated abdominal hyperalgesia in CP rats. The p-GluN2B expression was also suppressed by PKC inhibitor. Taken together, our results suggest that the upregulation of CBS in the ARC leads to an activation of GluN2B via PKCγ, which may play an important role in generation of pain hypersensitivity of CP.
Acute Disease ; Animals ; Arcuate Nucleus of Hypothalamus ; Cystathionine beta-Synthase ; Hyperalgesia ; Male ; Pain ; Pancreatitis, Chronic ; Phosphorylation ; Protein Kinase C ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; Up-Regulation

Kisspeptin signaling at the gonadotropin-releasing hormone (GnRH) neuron is now relatively well characterized and established as being critical for the neural control of fertility. However, kisspeptin fibers and the kisspeptin receptor (KISS1R) are detected throughout the brain suggesting that kisspeptin is involved in regulating the activity of multiple neuronal circuits. We provide here a review of kisspeptin actions on neuronal populations throughout the brain including the magnocellular oxytocin and vasopressin neurons, and cells within the arcuate nucleus, hippocampus, and amygdala. The actions of kisspeptin in these brain regions are compared to its effects upon GnRH neurons. Two major themes arise from this analysis. First, it is apparent that kisspeptin signaling through KISS1R at the GnRH neuron is a unique, extremely potent form or neurotransmission whereas kisspeptin actions through KISS1R in other brain regions exhibit neuromodulatory actions typical of other neuropeptides. Second, it is becoming increasingly likely that kisspeptin acts as a neuromodulator not only through KISS1R but also through other RFamide receptors such as the neuropeptide FF receptors (NPFFRs). We suggest likely locations of kisspeptin signaling through NPFFRs but note that only limited tools are presently available for examining kisspeptin cross-signaling within the RFamide family of neuropeptides.
Amygdala ; Arcuate Nucleus of Hypothalamus ; Brain ; Central Nervous System* ; Dopamine ; Fertility ; Gonadotropin-Releasing Hormone ; Hippocampus ; Humans ; Neurons* ; Neuropeptides ; Neurotransmitter Agents ; Oxytocin ; Synaptic Transmission ; Vasopressins

The present study was aimed to explore the effects of intraperitoneal injection of growth hormone releasing peptide-6 (GHRP-6), a ghrelin receptor agonist, on food intake and neuronal activity of feeding-related nuclei in the hypothalamus of NMRI mice. Accumulated amount of food intake was measured, and total number of c-fos immunoreactive neurons in arcuate nucleus (ARC), paraventricular nucleus (PVN) and supraoptic nucleus (SON) was counted by immunohistochemistry at 1, 3 and 6 h after the GHRP-6 injection. The results showed that GHRP-6 significantly increased the amount of food intake with a peak at 3 h after the GHRP-6 injection. Meanwhile, GHRP-6 could promote c-fos expression in the ARC and PVN independent of food intake, and the total number of c-fos immunoreactive neurons was peaked at 1 h after injection and then decreased gradually. These results suggest that GHRP-6 may increase food intake in time-dependent manner, which is associated with up-regulations of c-fos protein expression in the ARC and PVN.
Animals ; Arcuate Nucleus of Hypothalamus ; Eating ; Immunohistochemistry ; Male ; Mice ; Neurons ; Oligopeptides ; Paraventricular Hypothalamic Nucleus ; Proto-Oncogene Proteins c-fos ; Receptors, Ghrelin ; Supraoptic Nucleus

BACKGROUND: The melanocortin 4 receptor (MC4R) is involved in the regulation of homeostatic energy balance by the hypothalamus. Recent reports showed that MC4R can also control the motivation for food in association with a brain reward system, such as dopamine. We investigated the expression levels of MC4R and the dopamine D2 receptor (D2R), which is known to be related to food rewards, in both the hypothalamus and brain regions involved in food rewards. METHODS: We examined the expression levels of D2R and MC4R by dual immunofluorescence histochemistry in hypothalamic regions and in the bed nucleus of the stria terminalis (BNST), the central amygdala, and the ventral tegmental area of transgenic mice expressing enhanced green fluorescent protein under the control of the D2R gene. RESULTS: In the hypothalamic area, significant coexpression of MC4R and D2R was observed in the arcuate nucleus. We observed a significant coexpression of D2R and MC4R in the BNST, which has been suggested to be an important site for food reward. CONCLUSION: We suggest that MC4R and D2R function in the hypothalamus for control of energy homeostasis and that within the brain regions related with rewards, such as the BNST, the melanocortin system works synergistically with dopamine for the integration of food motivation in the control of feeding behaviors.
Amygdala ; Animals ; Arcuate Nucleus ; Brain* ; Dopamine* ; Eating* ; Feeding Behavior ; Fluorescent Antibody Technique ; Homeostasis ; Hypothalamus ; Mice ; Mice, Transgenic ; Motivation ; Obesity ; Receptor, Melanocortin, Type 4* ; Receptors, Dopamine D2* ; Reward ; Ventral Tegmental Area

Kisspeptins are a group of peptide fragments encoded by the KISS1 gene in humans. They bind to kisspeptin receptors with equal efficacy. Kisspeptins and their receptors are expressed by neurons in the arcuate and anteroventral periventricular nuclei of the hypothalamus. Oestrogen mediates negative feedback of gonadotrophin-releasing hormone secretion via the arcuate nucleus. Conversely, it exerts positive feedback via the anteroventral periventricular nucleus. The sexual dimorphism of these nuclei accounts for the differential behaviour of the hypothalamic-pituitary-gonadal axis between genders. Kisspeptins are essential for reproductive function. Puberty is regulated by the maturation of kisspeptin neurons and by interactions between kisspeptins and leptin. Hence, kisspeptins have potential diagnostic and therapeutic applications. Kisspeptin agonists may be used to localise lesions in cases of hypothalamic-pituitary-gonadal axis dysfunction and evaluate the gonadotrophic potential of subfertile individuals. Kisspeptin antagonists may be useful as contraceptives in women, through the prevention of premature luteinisation during in vitro fertilisation, and in the treatment of sex steroid-dependent diseases and metastatic cancers.
Animals ; Arcuate Nucleus of Hypothalamus ; metabolism ; Estrogens ; metabolism ; Feedback, Physiological ; Female ; Fertilization in Vitro ; Gonadotropin-Releasing Hormone ; metabolism ; Homeostasis ; Humans ; Kisspeptins ; physiology ; Male ; Mice ; Neoplasms ; metabolism ; Neurons ; metabolism ; Protein Binding ; Rats ; Reproduction ; Sex Factors ; Signal Transduction

OBJECTIVETo explore the expressions and functions of the kisspeptin/kiss1r system and GnRH in the hypothalamic arcuate nucleus (HAN) and the influence of the kisspeptin/kiss1r system on the hypothalamic-pituitary-testis (HPT) axis in the rat models of diet-induced obesity.

METHODSNinety newborn SD male rats were randomly assigned to receive normal diet (n = 30) and high-fat diet (n = 60) for the establishment of obesity models. The model rats were again equally divided into a control group and an experimental group, the latter injected with kisspeptin via the lateral ventricle. Then the body mass index (BMI) and endocrine hormone levels of the rats were recorded, the protein expressions of LepR, kisspeptin, kiss1r, and GnRH in the HAN determined by immunohistochemistry and Western blot, and the levels of GnRH mRNA in the HAN measured by qRT-PCR.

RESULTSSignificantly increased BMI and hormone levels indicated the successful establishment of diet-induced obesity models. Compared with the normal rats, the protein expressions of LepR, kisspeptin, and GnRH in the HAN were markedly decreased in the controls, and that of GnRH and the levels of LH and T significantly increased, but the expressions of LepR and kiss1r showed no remarkable changes in the experimental rats.

CONCLUSIONLateral ventricular injection of kisspeptin can upregulate obesity-induced low expression of GnRH, correct the dysfunction of the HPT axis, and thus improve reproductive function in rats.

Animals ; Arcuate Nucleus of Hypothalamus ; metabolism ; Diet, High-Fat ; Disease Models, Animal ; Female ; Gonadotropin-Releasing Hormone ; metabolism ; Hypothalamo-Hypophyseal System ; Kisspeptins ; metabolism ; Male ; Obesity ; metabolism ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; metabolism ; Receptors, Kisspeptin-1 ; Receptors, Leptin ; metabolism

OBJECTIVE: Stress is known to be an inhibitor of the reproductive hypothalamic-pituitary-gonadal (HPG) axis. However, the neural and molecular connections between stress and reproduction are not yet understood. It is well established that in both humans and rodents, kisspeptin (encoded by the kiss1 gene) is a strong stimulator of the HPG axis. In the present study we hypothesized that endocannabinoids, an important neuromodulatory system in the brain, can act on the HPG axis at the level of kiss1 expression to inhibit reproductive function under stress. METHODS: Adult male Wistar rats were unilaterally implanted with an intracerebroventricular cannula. Afterwards, the animals were exposed to immobilization stress, with or without the presence of the cannabinoid CB1 receptor antagonist AM251 (1 microg/rat). Blood samples were collected through a retro-orbital plexus puncture before and after stress. Five hours after the stress, brain tissue was collected for reverse transcriptase-quantitative polymerase chain reaction measurements of kiss1 mRNA. RESULTS: Immobilization stress (1 hour) resulted in a decrease in the serum luteinizing hormone concentration. Additionally, kiss1 gene expression was decreased in key hypothalamic nuclei that regulate gonadotrophin secretion, the medial preoptic area (mPOA), and to some extent the arcuate nucleus (ARC). A single central administration of AM251 was effective in blocking these inhibitory responses. CONCLUSION: These findings suggest that endocannabinoids mediate, at least in part, immobilization stress-induced inhibition of the reproductive system. Our data suggest that the connection between immobilization stress and the HPG axis is kiss1 expression in the mPOA rather than the ARC.
Adult ; Animals ; Arcuate Nucleus ; Axis, Cervical Vertebra* ; Brain ; Cannabinoids ; Catheters ; Endocannabinoids* ; Gene Expression ; Humans ; Immobilization ; Kisspeptins ; Luteinizing Hormone ; Male* ; Polymerase Chain Reaction ; Preoptic Area ; Punctures ; Rats* ; Rats, Wistar ; Receptor, Cannabinoid, CB1 ; Reproduction ; RNA, Messenger ; Rodentia