Leptin resistance in obese humans: does it exist and what does it mean?
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Animals↗
Biomedical subjects
M J Stock
Publications and source records attributed to M J Stock.
Thermogenic effects of sibutramine in humans.
BACKGROUND: Sibutramine is an effective compound for the treatment of obesity, acting both on serotonergic and noradrenergic pathways. Animal studies have shown that sibutramine exerts its effect by enhancing satiety as well as by increasing thermogenesis. OBJECTIVE: We tried to compare the acute thermogenic effect of a single 30-mg dose of sibutramine with placebo on basal energy expenditure (EE) and diet-induced thermogenesis. DESIGN: The study was randomized, double-blind, and placebo controlled. Eleven healthy, normal-weight men underwent 4 distinct treatment regimens separated by washout periods of 6-10 d. EE was measured by indirect calorimetry before and for 5.5 h after sibutramine or placebo administration with or without a 2.1-MJ breakfast. Visual analogue scales for assessment of appetite were completed hourly. RESULTS: Sibutramine caused a significant increase in EE above that for placebo (over 5.5 h) during both the fed (34%, 0.15 kJ/min) and fasted (183%, 0.20 kJ/min) states (P < 0.02) as well as during the last 3.5 h of this 5.5-h period and in the fed (87%, 0.26 kJ/min) and fasted (152%, 0.22 kJ/min) states, respectively (P < 0.01). The sibutramine-induced increase in EE was accompanied by an increase in plasma epinephrine (P < 0.01), heart rate (P < 0.001), blood pressure (P < 0.05), and plasma glucose (P < 0.02). About 25% of the increased heart rate with sibutramine could be explained by increased thermogenesis. Sibutramine increased satiety more than did placebo (5-h area under the curve, P < 0.05). CONCLUSIONS: Sibutramine caused a significant increase in both EE and satiety, which may both contribute to its weight-reducing properties.
Adult↗
Hyperphagia in cold-exposed rats is accompanied by decreased plasma leptin but unchanged hypothalamic NPY.
Chronic cold exposure stimulates sympathetically driven thermogenesis in brown adipose tissue (BAT), resulting in fat mobilization, weight loss, and compensatory hyperphagia. Hypothalamic neuropeptide Y (NPY) neurons are implicated in stimulating food intake in starvation, but may also suppress sympathetic outflow to BAT. This study investigated whether the NPY neurons drive hyperphagia in rats that have lost weight through cold exposure. Rats exposed to 4 degrees C for 21 days weighed 14% less than controls maintained at 22 degrees C (P < 0.001). Food intake increased after 3 days and remained 10% higher thereafter (P < 0.001). Increase BAT activity was confirmed by 64, 96, and 335% increases in uncoupling protein-1 mRNA at 2, 8, and 21 days. Plasma leptin decreased during prolonged cold exposure. Cold-exposed rats showed no significant changes in NPY concentrations in any hypothalamic regions or in hypothalamic NPY mRNA at any time. We conclude that the NPY neurons are not activated during cold exposure. This is in contrast with starvation-induced hyperphagia, but is biologically appropriate since enhanced NPY release would inhibit thermogenesis causing potentially lethal hypothermia. Other neuronal pathways must therefore mediate hyperphagia in chronic cold exposure.
Acclimatization↗
Diet-induced loss of cyclic ovarian function at normal body weight in a rodent model for bulimia nervosa.
A bulimic rat model was used to test whether type and frequency of food intake mimicking that in human bulimia nervosa could disrupt oestrous cyclicity, induce an effect on glycoprotein (LH) structure, or affect both processes and if so, to determine whether any such effects were acute, or persisted after return to normal eating patterns. Voluntary hyperphagia was induced by offering female rats a varied and palatable choice of human food items--the 'cafeteria diet'. There were four groups: control (normal chow), obese (continuous cafeteria diet), post-obese (cafeteria diet, then fasted to reduce weight to that of controls) and binge (cafeteria alternated with normal diet every few days). Animals were maintained on these diets for 60 days (phase I). They were then given a GnRH challenge on day 2 of dioestrus of the cycle. Twenty-four hours later, half of the animals in each group were killed for assessment of effects on their reproductive organs. The remaining animals were returned to normal diets and kept for a further 40 days, when the GnRH challenge was repeated and the animals were killed 24 h later (phase II). All animals on the cafeteria diet in phase I exhibited significant disruption of oestrous cyclicity irrespective of body weight. LH released in response to the first GnRH challenge showed a prolonged half-life, and/or increased rate of secretion in the obese and post-obese groups but in the binge group the secretory/clearance properties resembled those of control animals. After the second GnRH challenge at the end of phase II, however, the LH of the binge group appeared to have different secretory or clearance characteristics, whereas that of the previously obese animals had returned to normal. These data show ovarian cyclicity was disrupted by hyperphagia and irregular eating, even at normal body weight. Relating ovarian function to pituitary output in terms of LH, the effects of the continuous cafeteria diet did not appear to persist in the animals that returned to normal diets, but in the binge group the effect, presumably of the diet manipulation, was manifested after return to a normal eating pattern. This finding suggests that irregular eating habits may exert a direct (and acute) effect on the ovary, but that effects on the pituitary (and LH glycoforms) take longer to be expressed, explaining many features of bulimia nervosa.
Analysis of Variance↗
Effect of clenbuterol on endocrine status and nitrogen and energy balance in food-restricted rats.
We administered clenbuterol as a dietary admixture (4 mg/kg diet) to three groups of male Wistar rats (n = 8) housed individually in metabolism cages and fed for 15 d at 110, 160, and 235% (ad libitum) of the estimated requirement for energy maintenance. Untreated groups at each level of energy intake and a baseline group were also included. In the diet-restricted rats, clenbuterol induced greater and more persistent increases in nitrogen balance, biological value, and net protein utilization than it did in the ad libitum-fed rats. Energy balance was increased by clenbuterol treatment in the diet-restricted rats, with no significant changes occurring in the ad libitum fed rats. Compared with untreated rats, clenbuterol reduced blood glucose in all diet groups and serum insulin in the ad libitum and the moderately restricted (160%) rats. Serum IGF-I was increased in the highly restricted (110%) rats. Corticosterone levels were increased by clenbuterol treatment in all diet groups. These results are consistent with previous results showing that clenbuterol can help improve growth, but they also show that clenbuterol can offset the effects of food restriction on protein and energy metabolism.
Adrenergic beta-Agonists↗
The contribution of classical (beta1/2-) and atypical beta-adrenoceptors to the stimulation of human white adipocyte lipolysis and right atrial appendage contraction by novel beta3-adrenoceptor agonists of differing selectivities.
The role of beta3- and other putative atypical beta-adrenoceptors in human white adipocytes and right atrial appendage has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine beta3-adrenoceptor (beta3AR) agonists with varying intrinsic activities and selectivities for human cloned betaAR subtypes. The ability to demonstrate beta1/2AR antagonist-insensitive (beta3 or other atypical betaAR-mediated) responses to CGP 12177 was critically dependent on the albumin batch used to prepare and incubate the adipocytes. Four aryloxypropanolamine selective beta3AR agonists (SB-226552, SB-229432, SB-236923, SB-246982) consistently elicited beta1/2AR antagonist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) that was a selective full beta3AR agonist elicited full lipolytic and inotropic responses that were sensitive to beta1/2AR antagonism, despite it having very low efficacies at cloned beta1- and beta2ARs. A component of the response to another phenylethanolamine selective beta3AR agonist (SB-215691) was insensitive to beta1/2AR antagonism in some experiments. Because no [corrected] novel aryloxypropanolamine had a beta1/2AR antagonist-insensitive inotropic effect, these results establish more firmly that beta3ARs mediate lipolysis in human white adipocytes, and suggest that putative 'beta4ARs' mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned betaARs which betaARs will mediate responses to agonists in tissues that have a high number of beta1- and beta2ARs or a low number of beta3ARs.
Adipose Tissue↗
A role for brown adipose tissue in diet-induced thermogenesis.
Measurement of energy balance during voluntary overeating in rats unequivocally establishes the quantitative importance of diet-induced thermogenesis in energy balance. Like cold-induced thermogenesis, this form of heat production involves changes in the activity of the sympathetic nervous system and brown adipose tissue which suggest that this tissue may determine metabolic efficiency and resistance to obesity.
Adipose Tissue, Brown↗
Sibutramine: a review of the pharmacology of a novel anti-obesity agent.
Sibutramine is a noradrenaline and 5-hydroxytryptamine reuptake inhibitor which causes weight loss in laboratory rodents via effects on both food intake and metabolic rate. Sibutramine's effects are predominantly mediated by two pharmacologically-active metabolites (its primary and secondary amines). Sibutramine and its active metabolites do not cause the release of monoamine neurotransmitters and do not have affinity for their receptors. Sibutramine dose-dependently inhibits 24 h food intake in rats by enhancing the natural physiological process of satiety. Sibutramine also stimulates thermogenesis in rats, producing sustained (> 6 h) increases in oxygen consumption of up to 30%. The thermogenic effect of sibutramine results from central activation of efferent sympathetic activity which, in turn, involves activation of beta 3-adrenoceptors. Sympathetic stimulation of brown adipose tissue via beta 3-adrenoceptors is thought to be the cause of the large, 18 fold increase in brown adipose tissue glucose utilization induced by sibutramine. These dual effects of sibutramine on food intake and thermogenesis explain its anti-obesity effect in animals.
Adipose Tissue, Brown↗
Leptin activation in hypothalamus.
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Animals↗
Effect of selective beta-adrenoceptor stimulation on UCP synthesis in primary cultures of brown adipocytes.
Given the co-existence of the three beta-adrenoceptor (beta AR) subtypes (beta 1AR, beta 2AR and beta 3AR) in brown adipocytes, the present study was undertaken to determine the relative importance of these in the induction of UCP synthesis in mouse BAT precursor cells in primary culture. Cells at different stages of differentiation were exposed to different beta AR agonists: prenalterol (a selective beta 1AR agonist), salbutamol or clenbuterol (selective beta 2AR agonists), or BRL 37344 (a selective beta 3AR agonist). As with the endogenous agonist, noradrenaline, and the non-selective beta AR agonist, isoprenaline, all four beta AR agonists induced UCP in the confluent stage of the cells, but with different potencies, and with the highest induction being seen after clenbuterol or BRL 37344 treatment. Cells in the confluent stage of development were the most sensitive to the effects of the agonists, although clenbuterol and BRL 37344 induced a weak UCP synthesis in pre-confluent cells. None of these beta AR agonists were able to induce UCP synthesis in the post-confluent period. The responses to prenalterol and salbutamol were inhibited by propranolol at relatively low concentrations, suggesting their effects were mediated by beta 1AR and beta 2AR, respectively. However, propranolol was a particularly weak antagonist of BRL 37344 and, unexpectedly, of the clenbuterol UCP responses, which suggests that both induce UCP synthesis via the beta 3AR. In summary, the beta 3AR is the most important adrenoceptor coupled to the induction of UCP synthesis, although both beta 1AR and beta 2AR activation may make a contribution. However, all three beta AR subtypes do not become fully functional until cultured cells become confluent.
Adipose Tissue, Brown↗
Temperature-dependent effects of ephedrine in the cold.
This experiment examined the effects of intraperitoneal ephedrine (5-25 mg/kg) on operant thermoregulatory behavior of rats in the cold (-8 degrees C), and of 10 mg/kg on metabolic rate at a thermoneutral (22 degrees C) ambient temperature (Ta) and in the cold (5 degrees C). Posttest colonic temperature (Tc) decreased dose-dependently in the behavioral tests, yet the demand for heat varied little with respect to saline except for a significant reduction at the lowest dose tested (i.e., there was no compensation for the reduced Tc induced by ephedrine). Ephedrine had a potent thermogenic effect at a Ta of 22 degrees C, increasing both metabolic rate and Tc. In the cold, ephedrine reduced Tc, but this effect could not be accounted for by a reduction in metabolism, which was not significantly different from saline.
Animals↗
Biphasic effects of the beta-adrenoceptor agonist, BRL 37344, on glucose utilization in rat isolated skeletal muscle.
1. The effects of the selective beta 3-adrenoceptor agonist, BRL 37344 (BRL) on glucose uptake and phosphorylation (i.e. glucose utilization; GU) and glycogen synthesis in rat isolated soleus and extensor digitorium longus (EDL) muscle preparations in vitro were investigated by use of 2-deoxy-[3H]-glucose (GU) and [U-14C]-glucose (glycogen synthesis). 2. Low concentrations of BRL (10(-11)-10(-9) M) significantly increased GU, with maximal increases of 30% in soleus and 24% in EDL at 10(-11) M. Neither the selective beta 1-adrenoceptor antagonist, atenolol (10(-8)-10(-6) M), nor the selective beta 2-adrenoceptor antagonist, ICI 118551 (10(-8)-10(-6) M) had any effect on the stimulation of GU induced by 10(-11) M BRL. 3. High concentrations of BRL (10(-6)-10(-5) M) caused significant inhibition (up to 30%) of GU in both soleus and EDL muscles. The inhibition of 10(-6) M BRL was blocked completely by 10(-6) and 10(-7) M ICI 118551 in soleus, and by 10(-6)-10(-8) M ICI 118551 in EDL; atenolol (10(-8)-10(6) M) had no effect. 4. Another selective beta 3-adrenoceptor agonist, CL 316,243, also caused a significant stimulation of muscle GU, with maximal increases of 43% at 10(-9) M in soleus and 45% at 10(-10) M in EDL. The stimulation of GU declined with further increases in the concentration of CL 316,243, but no inhibition of GU was seen, even at the highest concentration (10(-5) M) tested. 5. BRL at 10(-5) M inhibited completely insulin-stimulated glycogen synthesis in both soleus and EDL, but this inhibitory effect of BRL was abolished by 10(-6) M ICI 118551. BRL at 10(-11) M (with or without 10(-6) M ICI 118551) had no effect on insulin-stimulated glycogen synthesis. 6. It is concluded that: (i) low (< nM) concentrations of BRL stimulate GU via an atypical beta-adrenoceptor that is resistant to conventional beta 1-adrenoceptor and beta 2-adrenoceptor antagonists; (ii) the stimulation of GU is negated by the activation of beta 2-adrenoceptors that occurs at higher (> nM) concentrations of BRL; (iii) inhibition of GU via beta 2-adrenoceptor activation is associated with inhibition of glycogen synthesis, possibly due to activation of glycogenolysis; (iv) the opposing effects of beta 2-adrenoceptor and atypical beta-adrenoceptor activation on GU suggest that in skeletal muscle these adrenoceptors are linked to different post-receptor pathways.
Adrenergic beta-Agonists↗
Inhibition of brown fat activity during hypothalamic stimulation in the rat.
Previous work has shown that low-level electrical stimulation of the ventromedial hypothalamus (VMH) in anesthetized rats produces a sustained decrease (phase 1) in interscapular brown adipose tissue (IBAT) temperature followed by a rise (phase 2) after the stimulus has stopped [Woods, A. J., and M. J. Stock. Am. J. Physiol. 266 (Regulatory, Integrative Comp. Physiol. 35): R328-R337, 1994]. In this study, rat oxygen consumption was found to decrease (24%) and then increase (74%) during phase 1 and 2, respectively. The effect of norepinephrine, alpha-adrenoceptor antagonists, substance P, and neuropeptide Y, with and/or without VMH stimulation, suggested that vasoconstriction was unlikely to account for the phase 1 decreases in thermogenesis and temperature. However, measurement with radio-labeled microspheres showed that IBAT capillary blood flow was reduced by 70% during phase 1, and this, plus a 50% decrease in blood oxygen extraction, indicated that phase 1 could be due to vasodilatation of arteriovenous anastomoses. It was postulated that phase 1 resulted from release of neuropeptides, such as substance P, causing diversion of arterial blood away from IBAT capillaries, thereby increasing convective heat loss and inhibiting heat production during phase 1.
Adipose Tissue, Brown↗
Effect of clenbuterol on growth and body composition during food restriction in rats.
Clenbuterol was administered as a dietary admixture (4 mg/kg diet) to three groups of male Wistar rats (n = 8) housed individually in metabolism cages and fed for 15 d at 110, 160, and 235% (ad libitum) of estimated requirement for energy maintenance. Untreated groups at each level of energy intake were also included. There was no effect of clenbuterol on food intake in the ad libitum group, but the drug produced significant increases in body weight, feed efficiency, and carcass weight, dressing and protein content at all three levels of energy intake. This effect of clenbuterol was particularly noticeable in the restricted animals. Clenbuterol caused changes in body composition (increased percentage of water and protein, decreased percentage of fat) in the ad libitum rats but had no effect in the restricted groups. The reduction in the growth of the viscera caused by energy restriction was not affected by clenbuterol, apart from in the 110% restricted group, where the gastrointestinal tract was 26% heavier in the clenbuterol-treated rats. The results show that the growth anabolic actions of clenbuterol can be sustained and may be even more marked in rats fed restrictively than in those given ad libitum access to feed.
Adrenergic beta-Agonists↗
Relationship between feeding pattern and body mass index in 220 free-living people in four age groups.
OBJECTIVE: To assess the relationship between feeding pattern and body mass index in free-living humans. DESIGN AND SUBJECTS: Feeding pattern was assessed from 220 7-day weighed dietary records. 187 records were obtained from three separate existing studies, and reanalysed. These studies contained data on three age groups in the British population; Elderly group (n = 88), Middle-aged group (n = 40), Working age group (n = 59). A separate study of 13-14 year olds living in Croydon was conducted from which 33 usable diet records were collected to produce a fourth, Adolescent group. RESULTS: 'Nibbling' and greater energy intakes at breakfast were associated with a lower body mass index (BMI) in the Adolescent group. In the Middle-aged group, greater energy intakes at breakfast and lower energy intakes during the evening were associated with a lower BMI. However, when diet records which produced unreasonably low energy intakes were removed from the analysis, these relationships disappeared except for energy intakes at breakfast and BMI in the Adolescent group. CONCLUSION: It is suggested that the relationship between feeding pattern and BMI observed in the Adolescent and Middle-aged groups was caused by underestimation of 'habitual' energy intake from snacks and the omission of breakfast by females and those who were overweight. The lack of relationship in the Working age group was attributed to the fact that more individuals in this group appeared to report valid diet records. Reported energy intake was directly related to BMI in the Working age group, but was not related to BMI in the other three age groups. It is concluded that feeding pattern is not a major factor in determining BMI in humans. Also, since snacks have a relatively high sugar and low fat composition compared with meals, it is suggested that biased under-reporting of snacks by the obese could produce spurious results from free-living studies which show that obesity is related to the proportion of energy from fat in the diet.
Adolescent↗
Effects of clenbuterol and salbutamol on tissue rubidium uptake in vivo.
In anesthetized rats, injection of the beta 2-adrenoceptor (beta 2-AR) agonist clenbuterol (0.45 mumol/kg) caused a marked stimulation of 86RbCl (Rb) uptake by skeletal muscle, but had no effect on other tissues; soleus muscle showed the largest (144% increase) response. Injection of another beta 2-AR agonist (salbutamol 0.45 mumol/kg) had no effect on Rb uptake by any tissue except soleus muscle (83%). Both agonists increased body (colonic) temperature to the same extent. A 3-day treatment with salbutamol as a dietary admixture had no effect on body weight, muscle mass, or tissue Rb uptake, whereas the same treatment using clenbuterol produced significant increases in body weight and muscle mass and significant decreases in Rb uptake in three of the four muscle groups studied; Rb uptake in soleus was not affected. In another experiment, the short-term effect of clenbuterol injection on muscle Rb uptake was found to be resistant to a high dose (20 mg/kg) of the selective beta 2-AR antagonist ICI 118551. It was concluded that the selective effects of short-term administration of clenbuterol on muscle Rb uptake, coupled with its effects over 3 days on Rb uptake and muscle hypertrophy, implicate beta-AR modulation of cation transport (possibly via Na,K-adenosine triphosphatase [ATPase] activity) in the anabolic effects of clenbuterol on muscle protein deposition. Since the stimulation of Rb uptake by clenbuterol was resistant to high doses of a selective beta 2-AR antagonist and since salbutamol had little or no effect on muscle hypertrophy or Rb uptake, it is suggested that clenbuterol may exert its effects via an atypical beta-AR.
Adipose Tissue, Brown↗
Acute effects of the beta 3-adrenoceptor agonist, BRL 35135, on tissue glucose utilisation.
1. The acute effects of BRL 35135 (BRL) on tissue glucose utilisation index (GUI) in vivo were investigated in anaesthetized rats by use of 2-deoxy-[3H]-glucose. 2. Intravenous injection of BRL caused a dose-dependent increase in GUI in skeletal muscle, and white and brown adipose tissue; plasma insulin and fatty acid concentrations were also increased. Chronic treatment with BRL added to the diet caused a 34 fold increase in basal GUI of brown adipose tissue (BAT), but had no effect on GUI in other tissues. After chronic treatment, the acute tissue response to an intravenous maximal dose of BRL had disappeared completely in all tissues apart from the soleus muscle. 3. A high dose (20 mg kg-1) of the non-selective beta-antagonist, propranolol, inhibited the acute effect of BRL on GUI in BAT, but failed to affect GUI in muscle. A lower dose (1 mg kg-1) of the antagonist also inhibited the BAT response, but had little or no effect on the response in Type I (working) muscles such as soleus and adductor longus (ADL), and potentiated the response in Type II (non-working) muscles such as tibialis and extensor digitorium longus (EDL). 4. A low dose (1 mg kg-1) of the selective beta 1-antagonist, atenolol, had no effect on the BRL response but the same dose of the selective beta 2-antagonist, ICI 118551, potentiated significantly the effect of BRL on GUI in most muscles without altering plasma insulin levels. 5. It is concluded that: (i) the heterogeneous tissue responses of different muscle fibre types in the presence of P-antagonists indicates that BRL affects muscle GUI directly, in addition to effects mediated by increases in plasma insulin concentration; (ii) the resistance of the BRL response to conventional P-adrenoceptor antagonists implicates an atypical adrenoceptor mediating the GUI response in skeletal muscle, but this may not be identical to the adipose tissue P3-adrenoceptor; (iii) the potentiation of BRL responses by ICI 118551 indicates an inhibitory P2-adrenoceptor-mediated component in the muscle GUI response to BRL.
Adipose Tissue↗
Sources of energy from meals versus snacks in 220 people in four age groups.
OBJECTIVES: To assess meals versus snacks in terms of their contribution to total daily energy intake (TDI), macronutrient composition, and food commodity profile. DESIGN AND SUBJECTS: Meals and snacks were assessed from 220 7-day weighed dietary records. 187 records were obtained from three separate existing studies, and reanalysed. These studies contained data on three different age groups in the British population; elderly group (n = 88), middle-aged group (n = 40), young adult group (n = 59). A separate study of 13-14-year-olds living in Croydon was conducted from which 33 usable diet records were collected (adolescent group). RESULTS: Boys in the adolescent group consumed more of their TDI as snacks (29.0%) compared with men in the young adult (18.9%) and elderly groups (16.6%), but not the middle-aged group (25.8%). Females consumed about the same percentage of their TDI as snacks; adolescent group 23.6%, young adult group 19.4%, middle-aged group 21.4%, elderly group 17.9%. Meals were higher in protein and fat, and lower in total sugars, compared with snacks. Chocolate confectionery, crisps and fizzy drinks and squashes were popular snack foods in the adolescent group. Unlike snacks, the food commodity profiles of meals were similar in all age groups. CONCLUSIONS: This study shows that foods and drinks consumed as snacks by the British public, including the elderly, have a relatively high total sugar composition. These results add to the concern relating snack foods with dental caries.
Adolescent↗