下丘脑黑皮质素系统对机体能量代谢的调控

下丘脑黑皮质素系统是中枢神经系统调控机体能量代谢的关键神经环路。既往研究证实其在调控机体摄食行为中发挥重要的作用,近几年的研究进一步阐明其在调控机体糖脂代谢中的作用和机制。最新的研究发现黑皮质素系统通过交感神经系统,调控棕色脂肪组织的产热以及白色脂肪米色化,在促进机体能量消耗的过程中发挥重要的作用。本文将主要对下丘脑黑皮质素系统及其相关的神经环路在调控机体能量代谢中的作用和机制对最新的研究进展做一综述,同时讨论临床抗肥胖和降糖药物的中枢作用机制,为对抗肥胖和糖尿病提供新思路。     

Effects of thyroxine on the photoperiodic control of energy balance and reproductive status in Siberian hamsters.

Siberian hamsters (Phodopus sungorus sungorus) exhibit a variety of seasonal responses when exposed to short days (SD), including decreases in body weight and fat, gonadal regression, and changes in several nonsteroid serum hormone concentrations. One such SD-induced hormonal change is a modest decrease in serum thyroxine (T4) concentrations. In an attempt to determine any underlying hormonal influences for the SD-induced decreases in body weight and fat, we investigated the possible role of T4 and triiodothyronine (T3). This potential paradoxical effect of these hormones on body weight and fat, as compared with most other rodent species, is not without precedent in Siberian hamsters. Specifically, changes in the gonadal steroids have opposite effects on body weight and fat in Siberian hamsters compared with laboratory rats and mice, and Syrian hamsters. SD serum thyroid hormone concentrations were elevated to long-day (LD) levels via subcutaneous T4 injections. Vehicle- and noninjected controls were included, as well as three similar LD-housed groups. Although we found a trend towards decreased T4 serum concentrations in noninjected control hamsters following 9 weeks of SD exposure, this effect did not reach statistical significance. SD-housed, T4-injected hamsters had similar decreases in body, fat pad, and paired testes weights compared to the SD-housed, vehicle- and noninjected controls despite having LD-like serum T4 and T3 concentrations. Thus, no paradoxical effect of the thyroid hormones on body weight (fat) was found, nor do these hormones appear to play a role in the effects of SDs on reproductive status in this hamster species.     

Hypothalamic and midbrain control of sexual receptivity in the female rat

The ventromedial nucleus of the hypothalamus (VMN) appears to be one site of action for estrogen with respect to the induction of sexual receptivity. Lateral efferents from the VMN pass through a region capping the lateral part of the cerebral peduncle and constitute a “lateral pathway” connecting the VMN with midbrain structures. Bilateral lesions of this peripeduncular region markedly reduced the display of lordosis by estrogen or estrogen-progesterone primed female rats in sex behavior tests with males. Sexual receptivity was comparably reduced when a sagittal knife-cut lateral to the VMN on one side of the brain was combined with a lesion of the peripeduncular region on the other side of the brain. In other words, asymmetric brain damage which nevertheless bilaterally interrupts axons of the lateral pathway connecting the VMN and midbrain markedly reduces the occurrence of lordosis, and we conclude that the integrity of the lateral pathway is essential for the hormonal induction of sexual receptivity in female rats. This pathway may be one avenue through which the action of estrogen on cells of the VMN may bias activity in midbrain structures directly concerned with the elicitation and/or execution of the lordosis reflex, to bring about the occurrence of sexual receptivity in the female.     

Hypothalamic osmoregulation is maintained across the wake–sleep cycle in the rat

In different species, rapid eye movement sleep (REMS) is characterized by a thermoregulatory impairment. It has been postulated that this impairment depends on a general insufficiency in the hypothalamic integration of autonomic function. This study aims to test this hypothesis by assessing the hypothalamic regulation of body fluid osmolality during the different wake–sleep states in the rat. Arginine‐vasopressin (AVP) plasma levels were determined following intracerebroventricular (ICV) infusions of artificial cerebrospinal fluid (aCSF), either isotonic or made hypertonic by the addition of NaCl at three different concentrations (125, 250 and 500 mm ). Animals were implanted with a cannula within a lateral cerebral ventricle for ICV infusions and with electrodes for the recording of the electroencephalogram. ICV infusions were made in different animals during Wake, REMS or non‐REM sleep (NREMS). The results show that ICV infusion of hypertonic aCSF during REMS induced an increase in AVP plasma levels that was not different from that observed during either Wake or NREMS. These results suggest that the thermoregulatory impairment that characterizes REMS does not depend on a general impairment in the hypothalamic control of body homeostasis.     

Endocannabinoid control of food intake and energy balance

Marijuana and its major psychotropic component, Delta(9)-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB(1) cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes.     

Mind versus metabolism in the control of food intake and energy balance

In a restrictive food environment, the homeostatic control system regulates body weight and adiposity with remarkable precision. However, this regulation appears to break down in many genetically predisposed individuals under conditions prevailing in the modern era characterized by a sedentary lifestyle and easy availability of large portions of palatable and calorically dense food. The nervous system is the main interface by which food-related environmental factors influence the regulatory process. Thus, focusing on the neural systems located in the telencephalon dealing with environmental factors, and on their connections with the homeostatic regulatory system distributed mainly in the hypothalamus and brainstem, should result in new drug targets and behavioral strategies for prevention and therapy. The structures providing this interface with the environment are involved in the initiation, procurement, and appetitive phases of ingestive behavior and associative learning before, during, and after the consummatory phase. It is thought that learned and unlearned representations of foods and food cues in the orbitofrontal and other cortical areas are filtered for affective/emotional value in the amygdala and for motivational salience in the nucleus accumbens/ventral striatum to initiate goal-directed motor programs. Internal state signals generated by the metabolic sensing mechanisms in the hypothalamus interact with each of these corticolimbic structures through reciprocal connections. While many projections from the hypothalamus contain the various "feeding peptides," the neurochemistry of projections to the hypothalamus has not been well characterized.     

Hypothalamic opioid-melanocortin appetitive balance and addictive craving

Whilst the parallels between drug and food craving are receiving increasing attention, the recently elucidated complex physiology of the hypothalamic appetite regulatory centres has been largely overlooked in the efforts to understand drug craving which is one of the most refractory and problematic aspects of drug and behavioural addictions. Important conceptual gains could be made by researchers from both appetite and addiction neuroscience if they were to have an improved understanding of each others' disciplines. It is well known in addiction medicine that the use of many substances is elevated in opiate dependency. There is voluminous evidence of very high rates of drug use in opiate agonist maintained patients, and the real possibility exists that opiate agonist therapy therefore increases drug craving. Conversely, opiate antagonist therapy with naloxone or naltrexone has been shown to reduce most chemical and behavioural addictions, and naltrexone is now being developed together with bupropion as the anti-obesity drug "Contrave". Hypothalamic melanocortins, particularly α-MSH, are known to constitute the main brake to consumptive behaviour of food. There is a well described antagonism between melanocortins and opioids at many loci including the hypothalamus. Administration of exogenous opiates is known to both suppress α-MSH and to stimulate hedonic food consumption. Opiate maintenance programs are associated with weight gain. As monoamines, opioids and cannabinoids are known to be involved in appetite regulation, and as endorphin opioids are known to be perturbed in other addictions, further exploration of the hypothalamic appetite regulatory centre would appear to be an obvious, albeit presently largely overlooked, locus in which to study drug and other craving mechanisms.     

Role of the glucagon-like-peptide-1 receptor in the control of energy balance

The peripheral and central glucagon-like-peptide-1 (GLP-1) systems play an essential role in glycemic and energy balance regulation. Thus, pharmacological targeting of peripheral and/or central GLP-1 receptors (GLP-1R) may represent a potential long-term treatment option for both obesity and type-II diabetes mellitus (T2DM). Uncovering and understanding the neural pathways, physiological mechanisms, specific GLP-1R populations, and intracellular signaling cascades that mediate the food intake inhibitory and incretin effects produced by GLP-1R activation are vital to the development of these potential successful therapeutics. Particular focus will be given to the essential role of the nucleus tractus solitarius (NTS) in the caudal brainstem, as well as the gut-to-brain communication by vagal afferent fibers in mediating the physiological and behavioral responses following GLP-1R activation.The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.     

Hypothalamic modulation of energy expenditure

The acute effects of electrical stimulation of the hypothalamus on energy expenditure as measured by indirect calorimetry were investigated in 20 unanaesthetized rats. Thirty sec of stimulation increased both O2 consumption and respiratory quotient (R.Q.). The largest magnitude hypermetabolic response (39% mean peak increase in O2 consumption) was produced by stimulation of the ventromedial hypothalamic nucleus. Stimulation of the lateral hypothalamus produced hypermetabolic effects similar to but smaller than those produced by medial stimulation. A number of considerations suggest that the hypermetabolism is not secondary to changes in motor activity, carbohydrate utilization or blood glucose levels. Consequently, these data suggest that the hypothalamus modulates energy expenditure through changes in non-shivering thermogenesis. These metabolic changes may modulate the effects of various hypothalamic manipulations on body weight.     

Homeostastic and non-homeostatic functions of melanocortin-3 receptors in the control of energy balance and metabolism

The central nervous melanocortin system is a neural network linking nutrient-sensing systems with hypothalamic, limbic and hindbrain neurons regulating behavior and metabolic homeostasis. Primary melanocortin neurons releasing melanocortin receptor ligands residing in the hypothalamic arcuate nucleus are regulated by nutrient-sensing and metabolic signals. A smaller group of primary neurons releasing melanocortin agonists in the nucleus tractus solitarius in the brainstem are also regulated by signals of metabolic state. Two melanocortin receptors regulate energy homeostasis. Melanocortin-4 receptors regulate satiety and autonomic outputs controlling peripheral metabolism. The functions of melanocortin-3 receptors (MC3R) expressed in hypothalamic and limbic structures are less clear. Here we discuss published data and preliminary observations from our laboratory suggesting that neural MC3R regulate inputs into systems governing the synchronization of rhythms in behavior and metabolism with nutrient intake. Mice subjected to a restricted feeding protocol, where a limited number of calories are presented at a 24 h interval, rapidly exhibit bouts of increased wakefulness and activity which anticipate food presentation. The full expression of these responses is dependent on MC3R. Moreover, MC3R knockout mice are unique in exhibiting a dissociation of weight loss from improved glucose homeostasis when subject to a restricted feeding protocol. While mice lacking MC3R fed ad libitum exhibit normal to moderate hyperinsulinemia, when subjected to a restricted protocol they develop hyperglycemia, glucose intolerance, and dyslipidemia. Collectively, our data suggest that the central nervous melanocortin system is a point convergence in the control of energy balance and the expression of rhythms anticipating nutrient intake.The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Pittsburg, July 2010.     

Hypothalamic control of thyrotrophin secretion

1. By means of the haemagglutination-inhibition technique, it has been possible to measure the plasma and pituitary levels of thyroid-stimulating hormone (TSH) following unilateral and bilateral electrolytic lesions placed in the supraoptic area of the hypothalamus of female rats.

2. Unilateral lesions after 8 and 48 hr caused a temporary decrease in the percentage of circulating TSH followed by a return to normal.

3. Bilateral lesions caused a fall in plasma TSH to a level 41% below normal at 10 days whereas the pituitary level increased 70%.

4. Rats with bilateral symmetrical supraoptic lesions, kept for 3 days at 4° C, had a lower plasma TSH content (23%) and a higher pituitary TSH content (16%) than the sham operated control animals but the levels of pituitary TSH did not show any significant difference (0·100 > P > 0·050).

5. Thyroidectomized rats with bilateral lesions kept at 26° C for 3 days had a much lower plasma TSH (39%) and a slightly higher pituitary TSH as compared to the normal intact animals, suggesting that the hypothalamus also influences the synthesis of TSH in the pituitary.

6. Thyroidectomized rats with bilateral lesions kept at 4° C for 3 days showed both a plasma and pituitary TSH increase compared to controls at 26° C, suggesting that when a higher demand for thyroid function is present the pituitary gland has some autonomy for both secretion and release of TSH. This autonomy appears to be slight, as there was no statistically significant difference between the pituitary TSH levels of the thyroidectomized animals bearing similar supraoptic lesions and exposed to 4 and 26° C.