Is Obesity or Adiposity-Based Chronic Disease Curable: The Set Point Theory,the Environment,and Second-Generation Medications

Adiposity-based chronic disease (ABCD) requires life-long treatment and follow up. Obesity protects obesity through altered regulation of caloric intake and set point mechanisms, which help maintain a high equilibrium body weight. Lifestyle interventions and obesity medications do not permanently alter the set point, which often makes weight loss achieved using lifestyle changes short-lived and operates to drive weight regain once medications are discontinued. Bariatric surgery procedures can alter appetite and lower the “set point” for the equilibrium body weight via unknown mechanisms. However, few patients attain an ideal body weight following surgery, many regain weight, and all require long-term follow up for the disease. The excess adiposity associated with ABCD gives rise to complications that impair health and confer morbidity and mortality; however, the genetic risks and potential interactions between genes and the environment that give rise to complications cannot be eliminated. The equilibrium body weight around which set point mechanisms operate can be modified by the environment, which underscores the importance of a less obesogenic environment for the prevention and treatment of ABCD on a population basis.Whether ABCD will eventually be curable will depend on a clear understanding of the molecular mechanisms that determine the set point regulation of body weight and the ability to permanently modulate the set point to oscillate around a lean body mass. However, the conceptualization of ABCD as a chronic disease does present us with opportunities for primary, secondary, and tertiary prevention to avert disease progression. For tertiary care, the advent of new, more effective second-generation obesity medications will allow clinicians to treat to target via active management of body weight into a target range that will ameliorate specific complications.     

Drugs of Dependence Though Not of Abuse: Fenfluramine and Imipramine

Measures of subjective feeling used by five patients indicated that depression of mood occurred about four days after fenfluramine withdrawal. An experiment in which another 11 patients took fenfluramine 80 mg for 28 days confirmed the depression, maximal on the fourth withdrawal day. It also indicated that in the first week of administration there was some mood elevation, but with feelings of impaired ability to concentrate. The drug reduced appetite and weight. A comparison is drawn with imipramine, which was found to induce initial and withdrawal changes of subjective experience (of dreaming) in six volunteers. It is suggested that certain mood-influencing drugs may not be drugs of abuse because of some unpleasant initial effects, though they can be drugs of dependence.     

Collateral fattening: When a deficit in lean body mass drives overeating

In his last review entitled “Some Adventures in Body Composition,” Gilbert Forbes reminded us that “lean body mass and body fat are in a sense companions.” To what extent the lean body mass (or fat‐free mass) component in this companionship impacts on energy intake is rarely a topic for discussion, amid a dominant adipocentric view of appetite control. Yet an analysis of the few human studies that have investigated the relationships between objectively measured food intake and body composition reveals a potentially important role for both an increase and a decrease in fat‐free mass in the drive to eat. These studies are highlighted here, together with the implications of their findings for research directed as much toward the elucidation of peripheral signals and energy‐sensing mechanisms that drive hunger and appetite, as toward understanding the mechanisms by which dieting and sedentariness predispose to fatness.     

Metabolic turnover rate: a physiological meaning of the metabolic rate per unit body weight.

In analogy to “specific gravity” or “specific heat” the expression “weight specific metabolic rate” (Ultsch, 1973) would be correct if the metabolic rate were directly proportional to body weight. In that case the quotient metabolic rate divided by body weight would be a constant, independent of body weight like density or specific heat are constants. The metabolic rate, however, is not proportional to body weight but to its $\text{3}\text{4}$ power. I have stated that heat flow per unit body weight has no proper physical or physiological meaning (Kleiber, 1970), but since found such a physiological meaning: in work with tracers turnover rates are measured as quotients of transfer rates/pool content. For similometric animals pool contents are proportional to body weight. For such animals therefore the quotient metabolic rate/body weight may have a proper physiological meaning, namely the turnover rate of chemical energy in the animal body.The usefulness of the turnover rate is limited. For the calculation of the energy requirement of horizontal animal locomotion, for example, the calculation from the metabolic rate per animal is preferable to the calculation based on the metabolic rate per unit body weight.     

Interactions of thyrotropin releasing hormone and morphine sulfate in rodents.

Thyrotopin releasing hormone (TRH) produces “wet dog shakes” in rats similar to those observed during morphine withdrawal. The shaking behavior precipitated by morphine abstinence can be exacerbated by TRH administration while the other components of the morphine withdrawal syndrome remain unchanged. Morphine, chlorpromazine, apomorphine, and Δ⁹-tetrahydrocannabinol effectively block shakes induced by either TRH administration or morphine withdrawal. These results suggest the possibility that endogenous TRH may be associated with the “wet dog shakes” observed as a portion of morphine's abstinence syndrome in rats. However, TRH is unable to alter the stereospecific binding of morphine $\text{in}$$\text{vivo}$ or $\text{in}$$\text{vitro}$, and naloxone fails to potentiate the number of TRH-induced shakes. TRH has no antinociceptive properties, and it cannot alter those of morphine. These data suggest that more than one neuromechanism may be responsible for shaking behavior in rats.     

RCT of a High‐protein Diet on Hunger Motivation and Weight‐loss in Obese Children: An Extension and Replication

This study aimed to evaluate the weight loss and hunger motivation effects of an energy‐restricted high‐protein (HP) diet in overweight and obese children. In total, 95 overweight and obese children attended an 8‐week (maximum) program of physical activity, reduced‐energy intake, and behavior change education. Children were randomly assigned to one of two isoenergetic diets (standard (SP): 15% protein; HP: 25% protein), based on individually estimated energy requirements. Anthropometry and body composition were assessed at the start and end of the program and appetite and mood ratings completed on the first 3 consecutive weekdays of each week children attended camp. The HP diet had no greater effect on weight loss, body composition, or changes in appetite or mood when compared to the SP diet. Overall, campers lost 5.2 ± 3.0 kg in body weight and reduced their BMI standard deviation score (sds) by 0.25. Ratings of desire to eat increased significantly over the duration of the intervention, irrespective of diet. This is the third time we have reported an increase in hunger motivation in weight‐loss campers and replicates our previous failure to block this with a higher protein diet. Further work is warranted into the management of hunger motivation as a result of negative energy balance.     

Inhibition of gastric emptying by peripheral and central fenfluramine in rats: Correlation with anorexia

Rats treated acutely with i.p. fenfluramine showed a profound inhibition of emptying of a chow meal from the stomach. This inhibition was attenuated by previous chronic treatment with fenfluramine. Tolerance to the gastric slowing occured with as few as 2–4 prior injections, a time course which closely matches tolerance to the anorectic effects of the drug. Cerebroventricular injections of fenfluramine and norfenfluramine in anorectic doses also inhibited gastric emptying.     

A dielectric theory of "multi-stratified shell" model with its application to a lymphoma cell

A theory of complex dielectric constant ($\text{ε}{}^1$) for the suspension of “multi-stratified” spherical particles is presented. Based on Maxwell's theory of interfacial polarization, we derive a general expression which correlates $\text{ε}{}^1$ with the electrical and geometrical parameters of each stratum. It can be shown that such a “multi-stratified” system in general should give rise to multiple dielectric dispersions, the number of which corresponds to the number of interfaces lying between the successive shell phases. The conditions for a full number of different “unit” dispersions to occur are also discussed. As an example, a special case of the “double-shell” model consisting of a spherical core and three layers of concentric phases is solved numerically by using a set of parameter values pertinent to a lymphoma cell. In light of the characteristic behavior of $\text{ε}{}^1$ thus revealed, we propose a scheme of procedure that applies to the determination of electrical parameters associated with the specific “double-shell” model.     

Serial Echocardiographic and Clinical Evaluation of Valvular Regurgitation Before,During, and After Treatment with Fenfluramine or Dexfenfluramine and Mazindol or Phentermine

RYAN, DONNA H., GEORGE A. BRAY, FRED HELMCKE, GARY SANDER, JULIA VOLAUFOVA, FRANK GREENWAY, PRAMILLA SUBRAMANIAM, AND D. LUKE GLANCY. Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine. Obes Res. Objective: The prevalence of cardiac valvular regurgitation demonstrated by echocardiography in patients who took appetite-suppressant medication for weight loss has been assessed at 5%-30%. We studied 86 patients who had echo-cardiograms before treatment with appetite suppressants to determine the incidence of new cases and to evaluate the clinical implication of the echocardiographic findings. Research Methods and Procedures: We studied 69 men [Mean± Standard Deviation (S) age 49±81] and 17 women (mean±S age 50±7) who had 233 echocardiograms before, during, and after a weight-loss program that used predominantly fenfluramine (or dexfenfluramine) with mazindol (or phentermine). Mean drug exposure was 17 months. Blinded echocardiographic readings were performed to identify and grade aortic regurgitation (AR) or mitral regurgitation (MR). Results: Seven of 86 patients (8%) had pre-existing regurgitation with five (6%) meeting our case definition. Thirteen (16. 5%) of initially normal patients developed valvular regurgitation and were new cases. Of the new cases, 12 were grade IAV AR and one was both grade II/III MR and IIDV AR. All 13 patients were asymptomatic, and only two aortic insufficiency murmurs could be auscultated. There was significantly greater risk for developing valvulopathy for those who took medications longer than 6 months (p = 0. 03), and no new cases were observed in patients exposed for less than 8 months. No increased risk associated with age, presence of hypertension, or exposure to fenfluramine-phentermine combination was demonstrated. Although there was a higher incidence of new regurgitation in women (31% vs. 13% for men), this was not statistically significant (p = 0. 093). Discussion: Some patients who had normal echocardiograms at baseline developed cardiac valvular regurgitation after exposure to fenfluramine or dexfenfluramine with mazindol or phentermine. The development of valvulopathy was significantly correlated with duration of exposure. The clinical implications of echocardiographically demonstrated regurgitation are uncertain, since there were only two audible murmurs and no other clinically relevant signs or symptoms among the patients.     

Long-term opiate receptor antagonism in a patient with panhypopituitarism: effects on appetite, prolactin and demand for vasopressin

As endogenous opiates are known to be involved in regulation of appetite, an obese patient with panhypopituitarism and frequent episodes of ravenous hunger was treated with the oral opiate antagonist naltrexone for 13 months. This resulted in loss of body weight and attacks of severe hunger. The increased serum prolactin concentration and the dose of vasopressin required for substitution could be reduced. Long-term application of opiate antagonists may be useful in related cases.     

Drug Withdrawal Syndromes: A Literature Review

Drug withdrawal syndromes reportedly have been caused by numerous pharmacological agents, but only a few drugs have been adequately studied in this regard. Criteria for evaluating drug withdrawal syndromes have been proposed. Sedative-hypnotic agents, opiates, corticosteroids, clonidine, tricyclic antidepressant medications and beta-adrenergic blocking agents meet the criteria for such syndromes. Gradual tapering of the dose of these drugs is recommended when therapy must be discontinued. Whether or not other drugs cause rebound reactions is questionable, but caution should be used when discontinuing drugs for which numerous reports of withdrawal syndromes exist.     

An appetite suppressant from Hoodia species

Studies conducted at the Council for Scientific and Industrial Research (CSIR, South Africa) identified extracts from Hoodia species, in particular Hoodia pilifera and Hoodia gordonii, as possessing appetite suppressing properties. Two pregnane glycosides were isolated by fractionation of the dried stems of H. gordonii. Their structures were determined as 3beta-[beta-D-thevetopyranosyl-(1-->4)-beta-D- cymaropyranosyl-(1-->4)-beta-D-cymaropyranosyloxy]-12beta-tigloyloxy-14beta-hydroxypregn-5-en-20-one (1) and 3beta-[beta-D-cymaropyranosyl-(1-->4)-beta-D-6-thevetopyranosyl-(1-->4)-beta-D-cymaropyranosyl-(1-->4)-beta-D-cymaropyranosyloxy]-12beta-tigloyloxy-14beta-hydroxypregn-5-en-20-one (2) on the basis of spectroscopic studies and conversion to known compounds. Compounds 1 and 2 were also isolated from H. pilifera. Compound 1 was tested for its appetite suppressant properties in rats by oral gavage at 6.25-50 mg/kg and the results showed that all doses resulted in a decrease of food consumption over an eight day period and a body mass decrease when compared to the control sample receiving only the vehicle. In a comparative study against a fenfluramine control sample, compound 1 resulted in a reduction in food intake over the study period, with a concomitant overall decrease in body weight while fenfluramine resulted in a small decrease in food intake, but an increase in body weight (though less than control group) over the same period of time.     

Short-term effects of a "health-at-every-size" approach on eating behaviors and appetite ratings

Objective: To assess the effects of a “Health‐At‐Every‐Size” (HAES) intervention on eating behaviors and appetite ratings in 144 premenopausal overweight women. Research Methods and Procedures: Women were randomly assigned to one of the 3 groups: HAES group, social support (SS) group, and control group (N = 48 in each group). Interventions were conducted over a 4‐month period, and measurements were taken before and after this period. Eating behaviors (cognitive dietary restraint, disinhibition, and susceptibility to hunger) were evaluated by the Three‐Factor Eating Questionnaire. Appetite ratings (desire to eat, hunger, fullness, and prospective food consumption) were assessed by visual analogue scales before and after a standardized breakfast. Results: More important decreases in susceptibility to hunger and external hunger were observed in the HAES group when compared with the SS group (p = 0.05, for susceptibility to hunger) and the control group (p = 0.02 and p = 0.005, for susceptibility to hunger and external hunger, respectively). In addition, women from the HAES group had more important decreases in postprandial area under the curve for desire to eat (p = 0.02) and hunger (p = 0.04) when compared with the control group. The change in the desire to eat noted in the HAES group was also different from the one observed in SS group (p = 0.02). Women from the HAES group experienced significant weight loss at 4 months (?1.6 ± 2.5 kg, p < 0.0001), which did not differ significantly from the SS and control groups (p = 0.09). An increase in flexible restraint was significantly related to a greater weight loss in both HAES and SS groups (r = ?0.39, p < 0.01; and r = ?0.37, p < 0.05, respectively). A decrease in habitual susceptibility to disinhibition was also associated with a greater weight loss in HAES and control groups (r = 0.31, p < 0.05; and r = 0.44, p < 0.05, respectively). Discussion: These results suggest that a HAES intervention could have significant effects on eating behaviors and appetite ratings in premenopausal overweight women, when compared with an SS intervention or a control group.     

Disparate effects of fenfluramine on thermogenesis in brown adipose tissue in the rat.

It has been suggested that fenfluramine, a clinically used appetite suppressant, can also promote weight loss by augmenting energy expenditure, as indicated by increased whole-body O2 consumption (VO2) and mitochondrial GDP binding in brown adipose tissue (BAT) of fenfluramine-treated rats. To further investigate a possible involvement of BAT in the drug's metabolic effects, 113Sn-labelled microspheres were injected into the left cardiac ventricle of conscious rats 70-80 min after intraperitoneal delivery of 20 mg/kg fenfluramine (DL-mixture) or saline vehicle. At 28 degrees C ambient temperature, fenfluramine augmented resting whole-body VO2 and increased the microsphere entrapment in BAT, indicating enhanced blood flow and metabolism. At 20 degrees C ambient temperature, the expected increase in BAT blood flow associated with nonshivering thermogenesis was observed in control rats, but in fenfluramine-treated rats the increase in BAT blood flow was severely attenuated, and VO2 and body temperature were reduced. The stimulatory effect of fenfluramine on BAT metabolism was not prevented by urethane anesthesia but did not occur if the tissue was denervated. These blood flow measurements corroborate previous reports, based on GDP-binding assays, that fenfluramine treatment can augment thermogenesis in BAT by effects mediated through the innervation of the tissue. However, the data also indicate that this calorigenic effect is dependent on ambient temperature being near thermoneutrality and that in a cool environment the drug inhibits BAT thermogenesis.     

Formation of pattern in regenerating tissue pieces of Hydra attenuata: I. Head-body proportion regulation

The precision with which an almost uniform sheet of hydra cells develops into a complete animal was measured quantitatively. Pieces of tissue of varying dimensions were cut from the body column of an adult hydra and allowed to regenerate. The regenerated animals were assayed for number of heads (hypostomes plus tentacle rings), head attempts (body tentacles), and basal discs. To ascertain whether the head and body were reformed in normal proportions, the average number of epithelial cells in the heads and bodies was measured. Pieces of tissue, from $\text{1}\text{2}$ to $\text{1}\text{20}$ an adult in size, formed heads that were a constant fraction of the regenerate. Thus, over a 10-fold size range, a proportioning mechanism was operating to divide the tissue into head area and body area quite precisely, but appeared to reach limits at the extremes of the range. However, the regenerates were not all normal miniatures with one hypostome and one basal disc. As the width-length ratio of the cut piece was increased beyond the circumference-length ratio of the intact body column, the incidence of extra hypostomes in the “head” and body tentacles and extra basal discs in the “body” rose dramatically. A proportioning mechanism based on the Gierer-Meinhardt model for pattern formation is presented to explain the results.     

The effect of silage additives containing formaldehyde on the fermentation of ryegrass ensiled at different dry matter levels and on the nutritive value of direct-cut silage

Ryegrass, harvested at the pre-ear emergence stage of growth, was ensiled in laboratory silos, either fresh (175 g dry matter kg^?1) or wilted to five DM levels ranging from 216–432 g DM kg^?1, with and without additive treatment. The additives used were “Sylade” containing sulphuric acid (15%) and formaldehyde (23%) applied at 4.6 l t^?1 and an “ADD-F” $\text{(85\%}\text{formic acid}\text{)}\text{formalin}$ mixture (7:3 by volume) applied at a similar rate (4.8 l t^?1). An additional treatment included application of the mixture at a constant rate related to the DM content of the ensiled crop (25 l t^?1 DM).In the untreated silages, the water-soluble carbohydrates (WSC) varied, respectively (over the DM range 175–432), from 0–32 g kg^?1 DM compared with 197-6 g kg^?1 DM for the “Sylade” treated silages and 256-50 g kg^?1 DM for the formic acid/formalin silages treated at an additive rate of 4.8 l t^?1. Corresponding ranges of protein N for the control and treatments (expressed as g kg^?1 total N) were 302–447, 624-502 and 620-505, respectively. When the formic acid/formalin additive was applied at a constant level related to the DM content of the crop, although the WSC content decreased with increasing DM (247-158 g kg^?1 DM), the protein N content (612 g kg^?1 total N) remained constant.Grass from the same field was ensiled fresh, treated with “ADD-F” at the rate of 3.4 l t^?1 fresh grass, $\text{“}\text{ADD-F}\text{”}\text{formalin}$ at the rate of 4.8 l t^?1 fresh grass and “Sylade” at the rate of 4.6 l t^?1 fresh grass. The silages were given to Suffolk-cross wether lambs in digestibility and intake trials. Digestibility coefficients of DM and energy of the silage treated with “Sylade” were significantly lower (P < 0.05) than those of the other three silages. The DM intakes of all the silages were high, ranging from 27.7 g kg^?1 live weight for the “Sylade” silage to 30.7 g kg^?1 live weight for the silage treated with $\text{“}\text{ADD-F}\text{”}\text{formalin}$. Live weight gains ranged from 200 g/day for the control silage to 267 g/day for the $\text{“}\text{ADD-F}\text{”}\text{formalin}$ silage.     

Eating Motives and the Controversy over Dieting: Eating Less Than Needed versus Less Than Wanted

Anti‐dieting sentiment has grown in recent years. Critics of restrained eating suggest that it evokes counter‐regulatory responses that render it ineffective or even iatrogenic. However, restrained eaters are not in negative energy balance and overweight individuals show reduced eating problems when losing weight by dieting. A distinction is often drawn between physiological and psychological hunger, and neuroscience research has shown that there is a neurophysiological reality underlying this distinction. The brain has a homeostatic system (activated by energy deficits) and a hedonic system (activated by the presence of palatable food). The omnipresence of highly palatable food in the environment may chronically activate the hedonic appetite system, producing a need to actively restrain eating not just to lose weight but to avoid gaining it. Just as restricting energy intake below homeostatic needs produces physiological deprivation, restricting intake of palatable foods may produce “perceived deprivation” despite a state of energy balance. In summary, the motivation to eat more than one needs appears to be every bit as real, and perhaps every bit as powerful, as the motivation to eat when energy deprived.     

A step towards developing the expertise to control hunger and satiety: Regulatory role of satiomem—A membrane proteoglycan

Regulation of hunger and satiety is a complex process thought to be controlled by a complex interplay of neurotransmitters in the hypothalamic region of the brain. Reduced food intake or anorexia has also been observed under various disease or disorder conditions including AIDS and cancer. On the other hand, increased appetite because of some impairment of central mechanisms regulating the food intake could also cause obesity. A large number of substances including neuropeptides, hormones, drugs, and synthetic peptides have been implicated in the regulation of appetite and food intake behavior in normal as well as disease or disorder conditions. Most of these substances are not directly involved in the regulation of normal hunger and satiety but exert their effect indirectly via other media. Some of them are involved under certain pathologic conditions and during the course they become involved directly or indirectly in the triggering of hunger and satiety regulatory mechanism. Recently, we have been able to isolate and purify an endogenous proteoglycan from membranes of animal and plant sources. This membrane anchored proteoglycan termed as Satiomem reduces food intake without any rebound effects and has no apparent toxicity. It also fulfils all the criteria of a true satiety or anorexigenic substance. The release of satiomem from the cell surface could be mediated by a specific phospholipase-C. Satiomem seems to be involved in transducing activating signals and may also act as a source of second messenger for the regulatory mechanism of appetite. This article summarizes the regulatory aspects of hunger and satiety mechanisms controlled by endogenous substances with the emphasis on our present knowledge about satiomem.Dedicated to Dr. Sydney Ochs.     

Reduction of lactic acid secreted from SV3T3 cells by a serum factor and biotin and its relationship to cell growth

Supplementation of media containing a low concentration (0.15–0.30% $\text{v}\text{>v}$) of calf serum with biotin or a low molecular weight serum growth factor (Peak III) reduces the amount of lactic acid secreted by simian virus 40-transformed 3T3 cells. While biotin and Peak III (which has been tentatively identified as biotin) can stimulate “stationary phase” cells to resume viable cell division, this growth promotion is not due to an alleviation of lactic acid toxicity per se. This conclusion is based on the finding that, although higher concentrations of lactic acid are cytotoxic, lactic acid added at concentrations found during “stationary phase” to cells plated in fresh medium is not growth inhibitory. These results suggest, instead, a possible major role for biotin and Peak III in energy production.