How does obesity affect the endocrine system? A narrative review.

Obesity is a chronic, relapsing medical condition that results from an imbalance of energy expenditure and consumption. It is a leading cause of preventable illness, disability and premature death. The causes of obesity are multifactorial and include behavioural, socioeconomic, genetic, environmental and psychosocial factors. Rarely are endocrine diseases, e.g., hypothyroidism or Cushing's syndrome, the cause of obesity. What is less understood is how obesity affects the endocrine system. In this review, we will discuss the impact of obesity on multiple endocrine systems, including the hypothalamic-pituitary axis, changes in vitamin D homeostasis, gender steroids and thyroid hormones. We will also examine the renin angiotensin aldosterone system and insulin pathophysiology associated with obesity. We will provide a general overview of the biochemical changes that can be seen in patients with obesity, review possible aetiologies of these changes and briefly consider current guidelines on their management. This review will not discuss endocrine causes of obesity.

Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 µg/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity.

NF-κB inhibition reveals a novel role for HGF during skeletal muscle repair.

The transcription factor nuclear factor κB (NF-κB)/p65 is the master regulator of inflammation in Duchenne muscular dystrophy (DMD). Disease severity is reduced by NF-κB inhibition in the mdx mouse, a murine DMD model; however, therapeutic targeting of NF-κB remains problematic for patients because of its fundamental role in immunity. In this investigation, we found that the therapeutic effect of NF-κB blockade requires hepatocyte growth factor (HGF) production by myogenic cells. We found that deleting one allele of the NF-κB subunit p65 (p65+/-) improved the survival and enhanced the anti-inflammatory capacity of muscle-derived stem cells (MDSCs) following intramuscular transplantation. Factors secreted from p65+/- MDSCs in cell cultures modulated macrophage cytokine expression in an HGF-receptor-dependent manner. Indeed, we found that following genetic or pharmacologic inhibition of basal NF-κB/p65 activity, HGF gene transcription was induced in MDSCs. We investigated the role of HGF in anti-NF-κB therapy in vivo using mdx;p65+/- mice, and found that accelerated regeneration coincided with HGF upregulation in the skeletal muscle. This anti-NF-κB-mediated dystrophic phenotype was reversed by blocking de novo HGF production by myogenic cells following disease onset. HGF silencing resulted in increased inflammation and extensive necrosis of the diaphragm muscle. Proteolytic processing of matrix-associated HGF is known to activate muscle stem cells at the earliest stages of repair, but our results indicate that the production of a second pool of HGF by myogenic cells, negatively regulated by NF-κB/p65, is crucial for inflammation resolution and the completion of repair in dystrophic skeletal muscle. Our findings warrant further investigation into the potential of HGF mimetics for the treatment of DMD.

Platelet monoamine oxidase-A activity and aging: effect of carnosine.

Platelet mitochondrial MAO-A activity of male albino rats (Wistar strain) was significantly inhibited with an inhibition of its only V max during aging. This age-induced inhibition of platelet MAO-A activity became reversed following the application of higher dosages (2.0-2.5 µg/kg/day, i.t. for 21 consecutive days) of carnosine. Though carnosine at lower dosage (0.5 µg/kg/day, i.t. for 21 consecutive days) was ineffective to platelet mitochondrial MAO-A activity in both young and aged rats, at higher dosages (2.0-2.5 µg/kg/day, i.t. for 21 consecutive days) under similar condition this enzyme activity was significantly enhanced. Carnosine at 1.0 µg/kg/day, i.t. for 21 consecutive days significantly enhanced MAO-A activity only in aged (18 and 24 months) rats. These results suggest that carnosine withdraws the aging-induced inhibition of mammalian blood platelet MAO-A activity and restores its activity towards that (MAO-A activity) observed in young mammalian blood platelets.

Aldrin-induced stimulation of locomotor activity and brain regional glutamate.

Single administration of aldrin (2-10 mg/kg) to adult male albino rats (120-130 g) enhanced locomotor activity (LA), with the maximum effect reached 2 h after treatment. The measurement of steady state levels of glutamate, glutamine and the activities of their metabolizing enzymes in different regions of the brains of rats treated with aldrin under its nontolerant condition showed that aldrin enhanced the activity of the neuronal glutamate system in the cerebral cortex, cerebellum and hypothalamus. Moreover, treatment with the glutamatergic NMDA receptor antagonist D,L-2-amino-7-phosphonoheptanoic acid, in the absence and presence of aldrin, reduced the LA of control rats and attenuated the aldrin-induced increase in LA of treated rats. These results suggest that aldrin-induced activation of the central glutamate system may be a cause of stimulation of LA with aldrin under its nontolerant condition.

Role of brain regional GABA: aldrin-induced stimulation of locomotor activity in rat.

Aldrin, a chlorinated hydrocarbon group of pesticide, is a well known central nervous system (CNS) stimulant. The CNS stimulating effect of aldrin is manifested in the form of an increase in locomotor activity (LA) of animals. Maximum increase in LA was observed at 2 h following aldrin (2-10 mg/kg, p.o.) treatment and this aldrin-induced increase in LA attained a peak at a dose of 10 mg/kg, p.o. Administration of aldrin (2 or 5 mg/kg/day, p.o.) enhanced LA of rats and reached a maxima after 12 consecutive days of treatment following which aldrin-induced LA was gradually reduced and restored to control value after 20 consecutive days of aldrin treatment. A single administration of aldrin (2-10 mg/kg, p.o.) reduced the GABA system in cerebellum, hypothalamus and pons-medulla. The treatment with aldrin (2 mg/kg/day, p.o.) for 12 consecutive days produced more inhibition in those brain regional GABA system than that observed with a single dose of aldrin. These results, thus, suggest that aldrin-induced inhibition of central GABA may be a cause of stimulation of LA with aldrin either at a single dose or for 12 consecutive days.

Long-term exposures to higher environmental temperature and body temperature: effect of chlorpromazine in relation to hypothalamic GABA.

Treatment with a single dose of chlorpromazine (CPZ; 1 mg/kg, ip) at room temperature (28 degrees +/-0.5 degrees C) significantly reduced body temperature by its anticholinergic action. Long-term exposures to higher environmental temperature (40 degrees +/-0.5 degrees C, 2 h/day, for 30 consecutive days) increased body temperature significantly by reduction of hypothalamic GABAergic activity, but this increase in body temperature was attenuated from that observed with a single exposure to higher environmental temperature (40 degrees C for 2 h). Treatment with a single dose of CPZ on the last day of 30 consecutive days of exposures to higher environmental temperature increased body temperature of rats more than that observed with long-term exposures to higher environmental temperature possibly due to (i) reduction of hypothalamic GABAergic activity, (ii) heat dissipation and (iii) reverse-anticholinergic action of CPZ at higher environmental temperature.

Age-associated hypothalamic glutamate receptor density: effect of dietary protein.

An age-associated (3-18 months) increase in hypothalamic glutamate receptor (HgluR) binding due to increase in receptor density (Bmax) was observed in rats maintained with normal (20%) protein diet. Short-term supplementation of low (5%) protein diet (LPD) and high (40%) protein diet (HPD) produced no significant change in the HgluR binding and Bmax in young as well as aged rats. Consumption of LPD for long-term period (LTP) increased the HgluR binding by increasing Bmax in young rats; whereas, intake of the same diet by the aged rats under similar condition reduced the HgluR binding by reducing Bmax. Unlike LPD, HPD intake by the young rats for LTP decreased the HgluR binding by decreasing affinity (1/KD) without altering Bmax. However, the aged rats when supplemented with HPD for LTP, the HgluR binding was increased due to increase in Bmax. Further, no age-induced increase in HgluR binding and Bmax was observed following short-term supplementation of LPD; whereas, long-term intake of LPD decreased the HgluR binding and Bmax in 18 months old rats compared to 3 months old rats under similar condition. On the other hand, HPD under LTP potentiated the age-induced increase in HgluR binding and Bmax. These results, thus, suggest that dietary protein affects the hypothalamic glutamatergic activity by modulating its receptor population depending on the age of the subject, quantity of dietary protein and its duration of supplementation.

Aldrin-induced locomotor activity: possible involvement of the central GABAergic-cholinergic-dopaminergic interaction.

Aldrin (5 mg/kg/day, p.o.) under nontolerant condition, administered either for a single day or for 12 consecutive days, enhanced locomotor activity (LA) of rats. The increase in LA was greater in rats treated with aldrin for 12 consecutive days than that observed with a single dose. The aim of the present study is to evaluate the involvement of possible interactions of central GABAergic, cholinergic and dopaminergic systems using their agonist(s) and antagonist(s) in the regulation of LA in aldrin nontolerant rats. Administration of either L-DOPA along with carbidopa or bicuculline potentiated aldrin-induced increase in LA under nontolerant condition as well as LA of the control rats. Treatment with muscimol, haloperidol, atropine or physostigmine all decreased the LA of both aldrin nontolerant and control rats. Further, the application of (a) haloperidol along with bicuculline, atropine or physostigmine and (b) physostigmine along with bicuculline or L-DOPA + carbidopa significantly reduced LA but L-DOPA + carbidopa along with atropine or bicuculline increased LA of the control rats. These agonist(s)/antagonist(s)-induced decrease or increase in LA of the control rats were attenuated or potentiated, respectively, when those agonist(s)/antagonist(s) under abovementioned condition were administered to aldrin nontolerant rats. The attenuating or potentiating effects of aldrin on agonist(s)/antagonist(s) (either individually or in different combinations)-induced change in LA were greater in rats treated with aldrin for 12 consecutive days than that observed with a single-dose aldrin treatment. These results suggest that aldrin, under nontolerant condition, reduces central GABAergic activity and increases LA by activating dopaminergic system via inhibition of cholinergic activity. The treatment with aldrin for 12 consecutive days produces greater effect than that caused by a single-day treatment.

Is age-induced decline in immune response associated with hypothalamic glutamate receptor density and dietary protein?

Manipulation of dietary protein has been found to be the most useful dictator in the age-associated decline of neuroimmune activity in mammals. In the present study, we sought to clarify the effect of dietary protein on age-induced alterations of hypothalamic glutamatergic activity and immune response. The hypothalamic glutamatergic activity and immune response were found to increase and decrease, respectively, with the increase in age of rats from young (3 months) to old (18 months) maintained with normal (20%) protein diet. Intake of low (5%) protein diet (LPD) and high (40%) protein diet (HPD) under short-term period (7 days) failed to alter the age-associated loss of immune response and increase in hypothalamic glutamatergic activity. However, long-term (30 days) supplementation of LPD retarded the age-induced decline in immune response and increase in hypothalamic glutamatergic activity, whereas, HPD consumption under similar condition potentiated the age-related immunosuppression and increase in hypothalamic glutamatergic activity. These results suggest that (a) the age-associated immunosuppression may be inversely related to the hypothalamic glutamatergic activity and (b) consumption of diets having variable quantity of protein without variation of calorie content modulates immune response and hypothalamic glutamatergic activity depending upon age and duration of dietary supplementation.

Long-term caffeine inhibits Ehrlich ascites carcinoma cell-induced induction of central GABAergic activity.

Long-term administration (for 22-27 consecutive days) of caffeine (20 mg/kg/day p.o) developed tolerance to this drug by upregulating the central GABAergic activity. Development of Ehrlich ascites carcinoma (EAC) cell induced the whole brain GABAergic activity. But pretreatment of caffeine and continuation of its treatment in the course of development of EAC cells restored the EAC cell-induced change of GABAergic activity to control values. Thus, it may be concluded that caffeine (adenosine receptor antagonist) suppresses the EAC cell-induced induction of whole brain GABAergic activity in mice.

Dietary protein alters age-induced change in hypothalamic GABA and immune response.

The effect of dietary protein on hypothalamic GABAergic activity and immune response of rats in relation to age was studied. The age-induced (due to increase of age from three to 18 months) decrease in hypothalamic GABAergic activity and immune response were potentiated with the supplementation of protein rich diet under both short- and long-term conditions. Long-term consumption of protein-poor diet, in contrast, produced activation of hypothalamic GABAergic activity with an immunopotentiation with the increase of age from three to 18 months; whereas, short-term supplementation of low protein diet did not show any effect. The results of the present study may indicate that the activation or inhibition of hypothalamic GABAergic activity by immunopotentiation or immunosuppression during aging depends on the variation of the amount of dietary protein as well as the duration of its supplementation.

Possible mechanism of interaction of GABAergic-adenosinergic systems in the regulation of theophylline-induced locomotor activity under its nontolerant and tolerant conditions.

The measurement of locomotor activity (LA) of theophylline (Th) nontolerant (10 mg/kg, p.o.) rats using agonist and antagonist of different neurotransmitters either in single or in their different combinations suggest that an inhibition of central GABAergic activity as well as adenosinergic and serotonergic activities through the stimulation of dopaminergic activity followed by an inhibition of cholinergic system may stimulate LA in Th nontolerant condition. Further, it is suggested that the development of tolerance to Th restored the LA to control value may be due to an activation of adenosinergic system which possibly withdrew the inhibition occurred in central cholinergic, GABAergic and serotonergic activities followed by the modulation of dopaminergic system.

Dietary protein-induced change in mammalian corticosterone status (index of immune response) during aging.

The measurement of corticosterone level in plasma and adrenal glands of male albino rats, maintained with normal diet (20% protein), increased with age from 3 to 18 months without changing its adrenal level. Intake of low protein diet (LPD) (5%) for short-term period of seven consecutive days (STP) increased the plasma and adrenal corticosterone level in 6 month old rats only and decreased only the adrenal corticosterone level in 9, 12 and 18 month old rats. LPD supplementation under long-term period (LTP) of 30 consecutive days increased the plasma corticosterone level with a decrease in its adrenal level in 3 month old rats. In 6 months old, the adrenal corticosterone was increased without affecting its plasma level; whereas in 18 month old rats, the plasma corticosterone level was decreased without affecting adrenal levels under similar conditions. High protein diet (HPD) (40%) consumption under STP conditions decreased the plasma corticosterone level in 3 month old rats and increased the same in 6 month old rats. The adrenal corticosterone level under similar condition was increased in 3 and 18 months old and decreased the same in 9 and 12 month old rats. Supplementation of HPD under LTP significantly decreased the plasma corticosterone in 3 and 9 month old rats, while its increase was observed only in 6 and 18 month old groups. The increase in adrenal corticosterone level was observed under similar conditions (HPD under LTP) in 3 the months old group and decreased the same in the 6 months old group. The present result thus suggest that the adrenocortical response may be modulated with the increase of age, the amount of protein supplemented in the diet and its duration of supplementation.

Hypothalamic GABA-ergic activity and T-cell proliferation in aged mammal: effect of dietary protein.

Short-term supplementation of low protein diet (LPD) or high protein diet (HPD) to the aged (18 months old) rats did not change the hypothalamic GABAergic activity and immune response. Long-term supplementation of LPD on the other hand, enhanced hypothalamic GABAergic activity with an immunopotentiation by increasing the T-cell proliferating activity and peripheral blood lymphocyte count in the same age group of rats. Unlike LPD, HPD under long-term supplementation to the aged rats reduced the hypothalamic GABAergic activity with immunosuppression. These results thus suggest that (i) hypothalamic GABAergic activity is a regulatory index of immune response in aged mammals and (ii) long-term consumption of protein-poor or protein-rich diet may be an exogenous modulator of neuroimmune regulation in relation to central GABAergic activity and immune response.

Is GABA involved in the development of caffeine tolerance?

Caffeine (10 or 20 mg/kg per day, po)-induced stimulation of locomotor activity (LA) reached its peak following 4 consecutive days of caffeine administration. Caffeine-induced stimulation of LA was restored to the control values following caffeine tolerance after 16 or 12 consecutive days of caffeine treatment at a dose of 10 or 20 mg/kg per day, po. Biochemical studies showed that caffeine in the nontolerant condition reduced GABAergic activity in cerebral cortex, corpus striatum, cerebellum, hypothalamus and pons-medulla; but tolerance to caffeine (10 or 20 mg/kg per day, po) pushed up the GABAergic activity to the control value in all these regions of brain. Further, it was found that muscimol reduced the LA while bicuculline stimulated LA in the caffeine tolerant condition. Thus, from the present study it may be concluded that: (a) caffeine-induced stimulation of LA is dependent on dose and duration of caffeine treatment, (b) development of tolerance to caffeine is dependent on the dosage of caffeine, and (c) the reduction of central GABAergic activity in the caffeine-nontolerant condition pushed up and restored the LA to the control level on the development of tolerance to caffeine.

Is hypothalamic GABA involved in immune function in relation to dietary protein during aging?

Hypothalamic GABAergic activity and immune response in spleen were not significantly changed with the increase of age from 3 to 6 months in adult male albino rats. Further increase of age from 6 to 9 months increase the GABAergic activity and decreased the cell viability in spleen without any change in its T-lymphocyte cytotoxicity. Consumption of low protein diet (LPD) for a short-term period (STP; 7 consecutive days) increased the hypothalamic GABAergic activity without changing the immune response in 3 months old rats. When supplemented for a long-term period (LTP; 30 consecutive days) to 3 months old rats, a reduction of hypothalamic GABAergic activity and the immune response was observed. Intake of high protein diet (HPD) for both STP and LTP increased the GABAergic activity and immune response, but the increase of GABAergic activity in hypothalamus under STP was greater than that observed under LTP. In 6 months old rats consumption of LPD for STP reduced the GABAergic activity without any alteration of its immune response. Long-term supplementation of this LPD to the same age group increased GABAergic activity and the mitotic activity of spleen cells without any alteration of the functional activity of the T-cells in spleen. Consumption of HPD for STP failed to produce any change in hypothalamic GABAergic activity and the immune response of 6 months old rats. Supplementation of HPD for LTP reduced the hypothalamic GABAergic activity and the immune response of the same age group. The reduction in hypothalamic GABAergic activity without any change in the immune response was observed following the supplementation of low protein diet to 9 months old rat for STP. Intake of the LPD for LTP also reduced the hypothalamic GABAergic activity and the mitotic activity of the spleen cells without any alteration of the functional activity of the T-cells in spleen of 9 months old rats. Supplementation of HPD for STP to this aged rat, on the other hand, failed to produced any change in hypothalamic GABAergic activity and the immune response. Intake of HPD for LTP by this aged rats increased the hypothalamic GABAergic activity along with the immune response. The results of this study, thus, suggest that hypothalamic GABAergic activity during aging is an index of immune response and it is modulated following the short- and long-term consumption of protein poor and protein rich diet.

Theophylline-induced changes in mammalian adenosine deaminase activity and corticosterone status: possible relation to immune response.

Theophylline at low doses (10 mg/kg/day p.o.) under long-term conditions (for 16 consecutive days) increased the adenosine deaminase (ADA) activity in spleen and thymus of adult male albino rats without changing its hepatic ADA activity. Treatment with high doses (20 mg/kg/day p.o.) under similar conditions, on the other hand, decreased the splenic and hepatic ADA activity and increased the thymic ADA activity. This induction of thymic ADA activity, however, was significantly less than that observed with low doses of theophylline. The plasma corticosterone level was increased without changing its adrenal level under similar conditions. This study, thus, indicates that long-term theophylline treatment may potentiate or suppress the immune response, depending on the dose, through the tissue (liver/spleen/thymus)-specific modulation of ADA activity and plasma corticosterone status.

Higher environmental temperature-induced increase of body temperature: involvement of central opioidergic-GABAergic interaction.

Exposure (2 h) of male albino rats to higher environmental temperature (HET, 40 degrees C) significantly increased the body temperature (BT). Administration of bicuculline (1 mg/kg, i.p.), physostigmine (0.2 mg/kg, i.p.), or their combination significantly raised the BT of normal rats (kept at 28 degrees C) or of HET-exposed rats. Atropine (5 mg/kg, i.p.) abolished the hyperthermic effect of bicuculline in normal and HET-exposed rats. The BT of normal and HET-exposed rat was increased with morphine (1 mg/kg, i.p.) and was reduced with naloxone (1 mg/kg, i.p.). Bicuculline or physostigmine-induced rise in BT of HET-exposed rats was potentiated following cotreatment of physostigmine with morphine. Atropine-induced hypothermia was abolished due to the cotreatment of atropine with morphine with physostigmine but was attenuated with atropine. In normal rats (kept at 28 degrees C), only atropine attenuated (morphine + bicuculline)-induced hyperthermia. L-Dopa + carbidopa or haloperidol did not significantly affect the BT of rats under similar conditions. These results suggest that short-term (2 h) exposure to HET activates the opioidergic neuron, which activates cholinergic activity through the inhibition of GABAergic system and, thus, enhances the BT.

Higher environmental temperature: effect of multiple exposures on long-term diazepam-induced changes in brain regional GABA.

The measurement of steady state level and accumulation rate of GABA and the activities of GAD and GABA-T in brain regions of adult male albino rats treated with diazepam (diazepam, 5 mg/kg/day, i.p.) and/or exposed (2 h/day) to higher environmental temperatures (higher environmental temperature, 40 degrees C) under long-term conditions (7-30 consecutive days) shows that long-term treatment with diazepam (5 mg/kg/day, i.p., for 15-30 consecutive days) reduced the GABAergic activity in the hypothalamus, corpus striatum (CS) and cerebellum (CM) without any alteration in the cerebrocortical region (CC). Multiple exposures to higher environmental temperatures for 7 consecutive days, on the other hand, enhanced GABAergic activity in hypothalamus, corpus striatum and cerebrocortical region of the rat. This higher environmental temperature-induced increase in GABAergic activity was further enhanced in the hypothalamus, but it was attenuated in the corpus striatum and became normalized in the cerebrocortical region upon the prolongation of exposure (15-30 consecutive days) to higher environmental temperature. The long-term diazepam-induced inhibition in GABAergic activity in hypothalamus and corpus striatum (but not in the cerebellum) disappeared and was finally activated following exposures (2 h/day) to higher environmental temperatures (40 degrees C) along with diazepam-treatment (5 mg/kg day, i.p.) for 7, 15 and 30 consecutive days. In the cerebellum, multiple exposures to higher environmental temperature did not significantly alter the long-term diazepam-induced inhibition of GABAergic activity or GABAergic activity in the normal rat.(ABSTRACT TRUNCATED AT 250 WORDS)