Body Weight Set Point Research Articles

Older adult women with chronic anorexia nervosa: heterogeneous adaptation to undernutrition over time.

Anorexia nervosa (AN) in older adult women is primarily described through reviews or case reports focusing on psychiatric traits, with no comprehensive studies evaluating their complete nutritional and hormonal profiles. This study aimed to describe a group of women with anorexia nervosa aged above 35 years old (AN35), and compare them with young women with anorexia nervosa (ANY) and normal-weight control participants. Anthropometric, metabolic, nutritional, and psychiatric parameters were collected and compared among three groups of women: 50 AN35, 37 ANY, and 38 controls. AN35 exhibited a mean disease duration of 271 ± 19 months, with 94% chronic forms and 58% restrictive types. Despite having similar BMI as ANY, AN35 displayed more altered parameters, including higher liver enzymes (p = 0.007), free T3 (p = 0.0046) and leptin (p < 0.0001); and lower albumin (p = 0.0029), and white cells (p < 0.0001). AN35 showed significant heterogeneity in hormonal adaptation, such as free T3. Half of the patients aged above 51 years revealed high gonadotropin levels despite being undernourished. Additionally, AN35 groups presented with 50% of bones fractures, decreased T-scores under -2.5 (p < 0.0001 for femoral), and altered micro architectural HRPQT parameters compared to ANY. Anorexia nervosa in older adult women is predominantly chronic. Nutritional parameters changes with age suggests a significant heterogeneity and possible adaptation of energy balance and bodyweight set point for others. Complications may be severe, altering the quality of life, and sometimes potentially lethal. These findings highlight the potential adaptation of energy balance with age, and should assist clinicians in clinical practice.

Branching out beyond canonical brown adipocyte function

Brown adipose tissue has long been functionally characterized as an organ that regulates thermogenesis, body weight set point, and glucose homeostasis. In the May 9, 2024, issue of Cell, Verkerke etal. discover a novel function for brown adipose tissue in processing branched-chain amino acids into antioxidant metabolites that enter the circulation and regulate insulin signaling in the liver.

Current and future pharmacotherapies for obesity in children and adolescents.

Obesity is a common chronic disease in children and adolescents and its prevalence is increasing worldwide. The causes are multifactorial but involve biological predisposition towards a specific body-weight set point and defended adipose tissue mass converging with an obesogenic environment. Comprehensive treatment of paediatric obesity includes lifestyle modification therapy, anti-obesity medications (AOMs) and/or metabolic surgery. Lifestyle modification therapy used alone produces fairly modest weight loss for most youth with obesity. The emergence of new AOMs has changed the landscape of paediatric weight management, improving the outlook for youth with obesity. This Review briefly highlights obesity development pathways in youth and the role that pharmacotherapy can play in counteracting these pathophysiological forces. Here, results from adolescent AOM clinical trials published since 2020 are reviewed, including the safety, efficacy and tolerability of the newest treatments (glucagon-like peptide 1 receptor agonists and phentermine-topiramate). The importance of a comprehensive and chronic care model, including both lifestyle modification and ongoing pharmacotherapy, will be discussed in the context of maximizing long-term health outcomes. Finally, insight will be provided into the emerging pipeline of AOMs (for example, incretin receptor co-agonists and tri-agonists) and how future therapies might fundamentally change the prognosis for youth with obesity.

High-fat diet-induced elevation of body weight set point in male mice.

High-fat diets (HFD) are thought to disrupt energy homeostasis to drive overeating and obesity. However, weight loss resistance in individuals with obesity suggests that homeostasis is intact. This study aimed to reconcile this difference by systematically assessing body weight (BW) regulation under HFD. Male C57BL/6 N mice were fed diets with varying fat and sugar in different durations and patterns. BW and food intake were monitored. BW gain was transiently accelerated by HFD (≥40%) prior to plateauing. The plateau was consistent regardless of starting age, HFD duration, or fat/sugar content. Reverting to a low-fat diet (LFD) caused transiently accelerated weight loss, which correlated with how heavy mice were before the diet relative to LFD-only controls. Chronic HFD attenuated the efficacy of single or repetitive dieting, revealing a defended BW higher than that of LFD-only controls. This study suggests that dietary fat modulates the BW set point immediately upon switching from LFD to HFD. Mice defend a new elevated set point by increasing caloric intake and efficiency. This response is consistent and controlled, suggesting that hedonic mechanisms contribute to rather than disrupt energy homeostasis. An elevated floor of the BW set point after chronic HFD could explain weight loss resistance in individuals with obesity.

Critical review of bariatric surgical outcomes in patients with Prader-Willi syndrome and other hyperphagic disorders

Brief Summary: This review analyzes the outcomes after bariatric procedures among patients with Prader-Willi syndrome (PWS), melanocortin 4 receptor (MC4R) mutations, Bardet-Biedl syndrome (BBS), and hypothalamic obesity (HO). The benefit of bariatric surgery in patients with hyperphagic disorders is only temporary or even absent, indicating the strength of perturbation in the regulation of energy homoeostasis in these patients leading to an elevated body weight set-point [9].

Epigenetics: Linking Early Postnatal Nutrition to Obesity Programming?

Despite constant research and public policy efforts, the obesity epidemic continues to be a major public health threat, and new approaches are urgently needed. It has been shown that nutrient imbalance in early life, from conception to infancy, influences later obesity risk, suggesting that obesity could result from “developmental programming”. In this review, we evaluate the possibility that early postnatal nutrition programs obesity risk via epigenetic mechanisms, especially DNA methylation, focusing on four main topics: (1) the dynamics of epigenetic processes in key metabolic organs during the early postnatal period; (2) the epigenetic effects of alterations in early postnatal nutrition in animal models or breastfeeding in humans; (3) current limitations and remaining outstanding questions in the field of epigenetic programming; (4) candidate pathways by which early postnatal nutrition could epigenetically program adult body weight set point. A particular focus will be given to the potential roles of breast milk fatty acids, neonatal metabolic and hormonal milieu, and gut microbiota. Understanding the mechanisms by which early postnatal nutrition can promote lifelong metabolic modifications is essential to design adequate recommendations and interventions to “de-program” the obesity epidemic.

Liraglutide Lowers Body Weight Set Point in DIO Rats and its Relationship with Hypothalamic Microglia Activation.

This study aimed to investigate the effects of liraglutide on thebody weight set point (BWSP) in diet-induced obese rats and to determine the relationship between BWSP and hypothalamic arcuate nucleus (ARC) microglial activation. Diet-induced obesity (DIO) rats were divided into three groups: continuous high-fat diet (HFD) plus saline, HFD with liraglutide, and HFD with liraglutide pair feeding. Body weight, BWSP, inflammatory cytokines, suppressor of cytokine signaling 3, orexigenic/anorexigenic proteins, apoptosis, and microglia in the ARC were assessed. The effect of liraglutide on the Notch-1 signaling pathway and its relationships with nuclear factor-κB and p38 mitogen-activated protein kinasewere also investigated in a lipopolysaccharide (LPS)-induced microglia activation model. Liraglutide reduced BWSP; reversed adverse changes in hypothalamic inflammation, suppressor of cytokine signaling 3, and apoptosis; and diminished microgliosis in DIO rats. The BWSP showed a linear correlation with ARC microglial density. Liraglutide inhibited LPS-induced M1 microglial polarization and promoted microglial polarization to theM2 phenotype, diminishing inflammatory cytokine expression. Liraglutide inhibited Notch-1 signaling pathway activation and decreased nuclear factor-κB and p38 mitogen-activated protein kinase pathway activation in LPS-stimulated microglia. Liraglutide can reduce BWSP in DIO rats. There is a linear correlation between hypothalamic microgliosis and BWSP. Liraglutide reduces excessive microglial activation and inflammation, which may contribute to BWSP reduction.

Effects of 17&amp;lt;i&amp;gt;β&amp;lt;/i&amp;gt;-Estradiol on Dopamine D2 Receptors in Thiamine-Deficient Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Our previous studies showed that 17β-estradiol (E2) modulated dopamine D2 receptor in regulating body weight set-point. The aim of this study was to understand whether thiamine deficiency influenced the E2 modulation on dopamine D2 receptors, using bromocriptine mesylate (BR) and sulpiride (SUL) as selective central dopamine-D2 receptors agonist and antagonist respectively. We studied the E2-dopamine D2 receptors interferences in a 10-day thiamine-deficient female rats for which consumptions of water, sugar, alcohol and food were daily-recorded and their consequences on body weights assessed. Our results showed that the volume of water daily ingested doubled in thiamine-deficient female rats (OXT), while sugar and alcohol consumptions collapsed with decreased weight and food consumption. On the one hand, thiamine potentiated D2/BR activity (bromocriptine-activated D2 receptors) to induce sugar intake and inhibited the same D2/BR receptors to induce water intake. On the other hand, thiamine promoted D2/SUL receptors (sulpiride-inhibited D2 receptors) for enhanced alcohol intake, increased food consumption and weight gain. Taking together, thiamine modulated the actions of 17β-estradiol on both D2/BR and D2/SUL receptors activities.

Effects of Ovariectomy and 17&amp;lt;i&amp;gt;β&amp;lt;/i&amp;gt;-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Background: Mechanisms underlying overeating-induced obesity in post-menopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or alcohol dependence through reward circuitry. This study aimed at further understanding 17β-estradiol and dopamine D2 receptors interferences in the etiology of woman obesity. Method: Seventy-two Wistar female rats weighing 200 - 205 g, individually-housed, were divided into non-ovariectomized control (C = 6 groups) and ovariectomized rats (OVX = 6 groups) which were concurrently subjected to the following treatments: Non-drug-treated (DMSO vehicle), 17β-estradiol (E2, 5 μg/kg, s.c.), sulpiride (SUL, 20 mg/kg, i.p.), bromocriptine (BR, 0.1 mg/kg, i.p.), E2 + SUL or E2 + BR, designating the 6 constitutive groups of either control or ovariectomy. Within each experimental group, consumption of different solutions (10% alcohol, 10% sucrose and water) as well as food intake and body weight were daily measured, for 10 consecutive days. Results: This study indicated that D2S was a specific inducer of alcohol and food intakes, but reduced sugar consumption. In addition, 17β- estradiol regulated the body weight set point, modulating D2S functions towards increased food intake at lower weights and decreased food intake at higher weights. D2S met the slow genomic actions induced by 17β-estradiol. Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels and promoting energy expenditure in reducing body weight. Indeed, 17β-estradiol exerted a tonic inhibition on D2L which was released by OVX, exacerbating sugar intake and increasing body weight. D2L mediated the rapid metabolic effects of 17β-estradiol. Conclusion: Our results supported physiological data reporting that activation of the mostly expressed presynaptically D2S-class autoreceptors decreased dopamine release stimulating food intake, whereas activation of the predominantly postsynaptic isoform D2L receptors increased dopamine activity inhibiting food intake. Our studies indicated that 17β-estradiol acted on the two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation. Our data also supported biochemical findings reporting that 17β-estradiol induced D2 genes transcriptional regulation, thereby involving both types of D2 receptors in the etiology of obesity. The combined dysregulated effects of D2L and D2S receptors, as 17β-estradiol was lacking, would be causal factors underlying the etiology of obesity.

Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling

The worldwide prevalence of obesity is increasing at an alarming rate but treatment options remain limited. Despite initial success, weight loss by calorie restriction (CR) often fails because of rebound weight gain. Postdieting hyperphagia along with altered hypothalamic neuro-architecture appears to be one direct cause of this undesirable outcome. In response to calorie deficiency the circulating levels of the appetite-promoting hormone, acyl-ghrelin, rise sharply. We hypothesize that proper modulation of acyl-ghrelin and its receptor's sensitivity will favorably impact energy intake and reprogram the body weight set point. Here we applied viral gene transfer of the acyl-ghrelin hydrolyzing enzyme, butyrylcholinesterase (BChE), in a mouse model of diet-induced obesity. Our results confirmed that BChE overexpression decreased circulating acyl-ghrelin levels, suppressed CR-provoked ghrelin signaling, and restored central ghrelin sensitivity. In addition to maintaining healthy body weights, BChE treated mice had modest postdieting food intake and showed normal glucose homeostasis. Spontaneous activity and energy expenditure did not differ significantly between treated and untreated mice after body weight rebound, suggesting that BChE gene transfer did not alter energy expenditure in the long term. These findings indicate that combining BChE treatment with CR could be an effective approach in treating human obesity and aiding lifelong weight management.

Making sense of metabolic obesity and hedonic obesity.

Body weight is neither stationary nor does it change unidirectionally. Rather, body weight usually oscillates up and down around a set point. Two types of forces determine the direction of weight changes. Forces that push body weight away from the set point are defined as non-homeostatic and are governed by multiple mechanisms, including, but not limited to, hedonic regulation of food intake. Forces that restore the set point weight are defined as homeostatic, and they operate through mechanisms that regulate short-term energy balance driven by hunger and satiation and long-term energy balance driven by changes in adiposity. In the normal physiological state, the deviation of body weight from the set point is usually small and temporary, and is constantly corrected by homeostatic forces. Metabolic obesity develops when body weight set point is shifted to an abnormally high level and the obese body weight becomes metabolically defended. In hedonic obesity, the obese body weight is maintained by consistent overeating due to impairments in the reward system, although the set point is not elevated. Adaptive increases in energy expenditure are elicited in hedonic obesity because body weight is elevated above the set point. Neither subtype of obesity undergoes spontaneous resolution unless the underlying disorders are corrected. In this review, the need for both appropriate patient stratification and tailored treatments is discussed in the context of the new framework of metabolic and hedonic obesity.

Does gastric bypass surgery change body weight set point?

The relatively stable body weight during adulthood is attributed to a homeostatic regulatory mechanism residing in the brain which uses feedback from the body to control energy intake and expenditure. This mechanism guarantees that if perturbed up or down by design, body weight will return to pre-perturbation levels, defined as the defended level or set point. The fact that weight re-gain is common after dieting suggests that obese subjects defend a higher level of body weight. Thus, the set point for body weight is flexible and likely determined by the complex interaction of genetic, epigenetic and environmental factors. Unlike dieting, bariatric surgery does a much better job in producing sustained suppression of food intake and body weight, and an intensive search for the underlying mechanisms has started. Although one explanation for this lasting effect of particularly Roux-en-Y gastric bypass surgery (RYGB) is simple physical restriction due to the invasive surgery, a more exciting explanation is that the surgery physiologically reprograms the body weight defense mechanism. In this non-systematic review, we present behavioral evidence from our own and other studies that defended body weight is lowered after RYGB and sleeve gastrectomy. After these surgeries, rodents return to their preferred lower body weight if over- or underfed for a period of time, and the ability to drastically increase food intake during the anabolic phase strongly argues against the physical restriction hypothesis. However, the underlying mechanisms remain obscure. Although the mechanism involves central leptin and melanocortin signaling pathways, other peripheral signals such as gut hormones and their neural effector pathways likely contribute. Future research using both targeted and non-targeted 'omics' techniques in both humans and rodents as well as modern, genetically targeted, neuronal manipulation techniques in rodents will be necessary.

Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity

ObjectiveA major challenge for obesity treatment is the maintenance of reduced body weight. Diet-induced obese mice are resistant to achieving normoweight once the obesogenic conditions are reversed, in part because lowered circulating leptin leads to a reduction in metabolic rate and a rebound of hyperphagia that defend the previously elevated body weight set point. Because hypothalamic POMC is a central leptin target, we investigated whether changes in circulating leptin modify Pomc expression to maintain normal energy balance in genetically predisposed obese mice. MethodsMice with reversible Pomc silencing in the arcuate nucleus (ArcPomc−/−) become morbidly obese eating low-fat chow. We measured body composition, food intake, plasma leptin, and leptin sensitivity in ArcPomc−/− mice weight-matched to littermate controls by calorie restriction, either from weaning or after developing obesity. Pomc was reactivated by tamoxifen-dependent Cre recombinase transgenes. Long acting PASylated leptin was administered to weight-reduced ArcPomc−/− mice to mimic the super-elevated leptin levels of obese mice. ResultsArcPomc−/− mice had increased adiposity and leptin levels shortly after weaning. Despite chronic calorie restriction to achieve normoweight, ArcPomc−/− mice remained moderately hyperleptinemic and resistant to exogenous leptin's effects to reduce weight and food intake. However, subsequent Pomc reactivation in weight-matched ArcPomc−/− mice normalized plasma leptin, leptin sensitivity, adiposity, and food intake. In contrast, extreme hyperleptinemia induced by PASylated leptin blocked the full restoration of hypothalamic Pomc expression in calorie restricted ArcPomc−/− mice, which consequently regained 30% of their lost body weight and attained a metabolic steady state similar to that of tamoxifen treated obese ArcPomc−/− mice. ConclusionsPomc reactivation in previously obese, calorie-restricted ArcPomc−/− mice normalized energy homeostasis, suggesting that their body weight set point was restored to control levels. In contrast, massively obese and hyperleptinemic ArcPomc−/− mice or those weight-matched and treated with PASylated leptin to maintain extreme hyperleptinemia prior to Pomc reactivation converged to an intermediate set point relative to lean control and obese ArcPomc−/− mice. We conclude that restoration of hypothalamic leptin sensitivity and Pomc expression is necessary for obese ArcPomc−/− mice to achieve and sustain normal metabolic homeostasis; whereas deficits in either parameter set a maladaptive allostatic balance that defends increased adiposity and body weight.

Depot- and sex-specific effects of maternal obesity in offspring's adipose tissue.

According to the Developmental Origin of Health and Disease (DOHaD) concept, alterations of nutrient supply in the fetus or neonate result in long-term programming of individual body weight (BW) setpoint. In particular, maternal obesity, excessive nutrition, and accelerated growth in neonates have been shown to sensitize offspring to obesity. The white adipose tissue may represent a prime target of metabolic programming induced by maternal obesity. In order to unravel the underlying mechanisms, we have developed a rat model of maternal obesity using a high-fat (HF) diet (containing 60% lipids) before and during gestation and lactation. At birth, newborns from obese dams (called HF) were normotrophs. However, HF neonates exhibited a rapid weight gain during lactation, a key period of adipose tissue development in rodents. In males, increased BW at weaning (+30%) persists until 3months of age. Nine-month-old HF male offspring was normoglycemic but showed mild glucose intolerance, hyperinsulinemia, and hypercorticosteronemia. Despite no difference in BW and energy intake, HF adult male offspring was predisposed to fat accumulation showing increased visceral (gonadal and perirenal) depots weights and hyperleptinemia. However, only perirenal adipose tissue depot exhibited marked adipocyte hypertrophy and hyperplasia with elevated lipogenic (i.e. sterol-regulated element binding protein 1 (Srebp1), fatty acid synthase (Fas), and leptin) and diminished adipogenic (i.e. peroxisome proliferator-activated receptor gamma (Pparγ), 11β-hydroxysteroid dehydrogenase type 1 (11β-Hds1)) mRNA levels. By contrast, very few metabolic variations were observed in HF female offspring. Thus, maternal obesity and accelerated growth during lactation program offspring for higher adiposity via transcriptional alterations of visceral adipose tissue in a depot- and sex-specific manner.

Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus.

Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks’ refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.

Calorie restriction-mediated restoration of hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation is not effective for lowering the body weight set point in IRS-2 knockout obese mice

Lowering the body weight set point is a prerequisite for the maintenance of reduced body weight. In this context, obesity is known to be strongly linked to leptin resistance, and it remains to be clarified whether recovery from leptin resistance might lower the body weight set point to allow sustained body weight loss. Obese IRS-2 knockout (IRS-2 −/−) mice were subjected to calorie restriction (CR) or β3-adrenergic receptor (AR) agonist treatment. The physiological effects of leptin, hypothalamic leptin signaling, and alterations of the body weight set point were evaluated. In the CR mice, recovery from acquired leptin resistance was observed, as shown by the restoration of the suppressive effects of leptin on food intake and weight gain, as well as the recovery of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Nevertheless, the body weight quickly rebounded to the original body weight after cessation of the CR, suggesting that CR failed to overcome the primary defect in IRS-2/phosphatidylinositol 3-kinase (PI3K) signaling. On the other hand, after 2 weeks β3-AR agonist treatment, the mice began to lose body weight, indicating that the treatment was able to overcome the primary defect in IRS-2/PI3K signaling and lower the body weight set point. Recovery of acquired leptin resistance does not lead to a resetting of the body weight set point in obese IRS-2/PI3K-defective mice. β3-AR agonist treatment may act on some pathways distal to or independent of PI3K and/or STAT3, inducing resetting of the body weight set point.

Metabolic vs. hedonic obesity: a conceptual distinction and its clinical implications.

SummaryBody weight is determined via both metabolic and hedonic mechanisms. Metabolic regulation of body weight centres around the ‘body weight set point’, which is programmed by energy balance circuitry in the hypothalamus and other specific brain regions. The metabolic body weight set point has a genetic basis, but exposure to an obesogenic environment may elicit allostatic responses and upward drift of the set point, leading to a higher maintained body weight. However, an elevated steady‐state body weight may also be achieved without an alteration of the metabolic set point, via sustained hedonic over‐eating, which is governed by the reward system of the brain and can override homeostatic metabolic signals. While hedonic signals are potent influences in determining food intake, metabolic regulation involves the active control of both food intake and energy expenditure. When overweight is due to elevation of the metabolic set point (‘metabolic obesity’), energy expenditure theoretically falls onto the standard energy–mass regression line. In contrast, when a steady‐state weight is above the metabolic set point due to hedonic over‐eating (‘hedonic obesity’), a persistent compensatory increase in energy expenditure per unit metabolic mass may be demonstrable. Recognition of the two types of obesity may lead to more effective treatment and prevention of obesity.

Nutrigenomics of body weight regulation: a rationale for careful dissection of individual contributors.

Body weight stability may imply active regulation towards a certain physiological condition, a body weight setpoint. This interpretation is ill at odds with the world-wide increase in overweight and obesity. Until now, a body weight setpoint has remained elusive and the setpoint theory did not provide practical clues for body weight reduction interventions. For this an alternative theoretical model is necessary, which is available as the settling point model. The settling point model postulates that there is little active regulation towards a predefined body weight, but that body weight settles based on the resultant of a number of contributors, represented by the individual’s genetic predisposition, in interaction with environmental and socioeconomic factors, such as diet and lifestyle. This review refines the settling point model and argues that by taking body weight regulation from a settling point perspective, the road will be opened to careful dissection of the various contributors to establishment of body weight and its regulation. This is both necessary and useful. Nutrigenomic technologies may help to delineate contributors to body weight settling. Understanding how and to which extent the different contributors influence body weight will allow the design of weight loss and weight maintenance interventions, which hopefully are more successful than those that are currently available.

The cellularity of offspring's adipose tissue is programmed by maternal nutritional manipulations

Epidemiological studies initially demonstrated that maternal undernutrition leads to low birth weight with increased risk of adult-onset obesity. Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates, and rapid catch-up growth also predispose offspring to fat accumulation. As stated by the Developmental Origin of Health and Disease concept, nutrient supply perturbations in the fetus or neonate result in long-term programming of individual body weight set-point. Adipose tissue is a key fuel storage unit mainly involved in the maintenance of energy homeostasis. Studies in numerous animal models have demonstrated that the adipose tissue is the focus of developmental programming events in a gender- and depot-specific manner. This review summarizes the impact of maternal nutritional manipulations on cellularity (i.e., cell number, size, and type) of adipose tissue in programmed offspring. In rodents, adipose tissue development is particularly active during the perinatal period, especially during the last week of gestation and during early postnatal life. In contrast to rodents, this process essentially takes place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several mechanisms of adipose tissue programming. Maternal nutritional manipulations result in increased adipogenesis and modified fat distribution and composition. Inflammation changes such as infiltration of macrophages and increased inflammatory markers are also observed. Overall, it may predispose offspring to fat accumulation and obesity. Inappropriate hormone levels, modified tissue sensitivity, and epigenetic mechanisms are key factors involved in the programming of adipose tissue's cellularity during the perinatal period.

Single rapamycin administration induces prolonged downward shift in defended body weight in rats.

Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.