Objectives The National Institutes of Health, led by the National Heart, Lung, and Blood Institute, organized a working group of experts to discuss the problem of weight regain after weight loss. A number of experts in integrative physiology and behavioral psychology were convened with the goal of merging their perspectives regarding the barriers to scientific progress and the development of novel ways to improve long-term outcomes in obesity therapeutics. The specific objectives of this working group were to: (1) identify the challenges that make maintaining a reduced weight so difficult; (2) review strategies that have been used to improve success in previous studies; and (3) recommend novel solutions that could be examined in future studies of long-term weight control. Results Specific barriers to successful weight loss maintenance include poor adherence to behavioral regimens and physiological adaptations that promote weight regain. A better understanding of how these behavioral and physiological barriers are related, how they vary between individuals, and how they can be overcome will lead to the development of novel strategies with improved outcomes. Conclusions Greater collaboration and cross-talk between physiological and behavioral researchers is needed to advance the science and develop better strategies for weight loss maintenance.

Ablation of peroxisome proliferator activated receptor (PPAR) ␣, a lipid-activated transcription factor that regulates expression of ␤-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR␣ knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR␣ target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR␦ is severalfold more abundant than either PPAR␣ or PPAR␥. In both human and rodent myocytes, the highly selective PPAR␦ agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR␣ agonist GW647. These results show redundancy in the functions of PPARs ␣ and ␦ as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the ␦-subtype can compensate for deficiency of PPAR␣.Peroxisome proliferator activated receptors (PPARs) 1 ␣, ␦, and ␥ comprise a family of nuclear hormone receptors that regulate systemic fatty acid metabolism via ligand-dependent transcriptional activation of target genes (1). Strong evidence indicates that their endogenous ligands consist of fatty acids and/or lipid metabolites and that they function to mediate adaptive metabolic responses to changes in systemic fuel availability (1, 2). PPAR␣, which is expressed most abundantly in tissues that are characterized by high rates of fatty acid oxidation (FAO), is considered the primary subtype that mediates lipid-induced activation of FAO genes (3). This premise is based largely on studies of PPAR␣ knockout (KO) mice, which, compared with wild type (WT) littermates, exhibit low rates of ␤-oxidation and abnormal accumulation of neutral lipids in both cardiac and hepatic tissues (4, 5). The metabolic phenotype of KO mice is associated with decreased expression of FAO genes and failure of liver and heart to induce ␤-oxidative pathways in response to physiological or pharmacological perturbations in lipid metabolism (4 -6). Taken together, these studies indicate that, at least in rodents,...

Dieting is the most common approach to losing weight for the majority of obese and overweight individuals. Restricting intake leads to weight loss in the short term, but, by itself, dieting has a relatively poor success rate for long-term weight reduction. Most obese people eventually regain the weight they have worked so hard to lose. Weight regain has emerged as one of the most significant obstacles for obesity therapeutics, undoubtedly perpetuating the epidemic of excess weight that now affects more than 60% of U.S. adults. In this review, we summarize the evidence of biology's role in the problem of weight regain. Biology's impact is first placed in context with other pressures known to affect body weight. Then, the biological adaptations to an energy-restricted, low-fat diet that are known to occur in the overweight and obese are reviewed, and an integrative picture of energy homeostasis after long-term weight reduction and during weight regain is presented. Finally, a novel model is proposed to explain the persistence of the "energy depletion" signal during the dynamic metabolic state of weight regain, when traditional adiposity signals no longer reflect stored energy in the periphery. The preponderance of evidence would suggest that the biological response to weight loss involves comprehensive, persistent, and redundant adaptations in energy homeostasis and that these adaptations underlie the high recidivism rate in obesity therapeutics. To be successful in the long term, our strategies for preventing weight regain may need to be just as comprehensive, persistent, and redundant, as the biological adaptations they are attempting to counter. energy restriction; diet-induced obesity; obesity prone; weight loss; energy balance IN THE UNITED STATES, OVER 60% of adults and close to 20% of children are overweight or obese (35,174). A number of effective weight loss strategies are available, but most are only transiently effective over a period of 3 to 6 mo. Less than 20% of individuals that have attempted to lose weight are able to achieve and maintain a 10% reduction over a year (128). Over one-third of lost weight tends to return within the first year, and the majority is gained back within 3 to 5 years (3,246). A number of reasons have been proposed for the high incidence of weight regain (69,246), and several point to the biological response to weight loss.The objective of this review is to examine the role of this biological response in the process of weight regain. Biological regulation is first discussed in relation to other nonbiological pressures that affect body weight as weight is gained, lost, and regained. The specific biological adaptations to the most common form of dieting, an energy-restricted low-fat diet, are then discussed in more detail. Previous reviews provide extensive descriptions of the normal adaptive response to energy restriction. We do not attempt to recapitulate those efforts here. Rather, the unique perspective of this review summarizes those adaptations that have been confirmed o...

Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome.ketohexokinase | hepatic steatosis | insulin | leptin

Objective To evaluate the safety and tolerability of alternate-day fasting (ADF) and to compare changes in weight, body composition, lipids, and insulin sensitivity index (Si) to those produced by a standard weight loss diet, moderate daily caloric restriction (CR). Methods Adults with obesity (BMI ≥30 kg/m2, age 18-55) were randomized to either zero-calorie ADF (n=14) or CR (-400 kcal/day, n=12) for 8 weeks. Outcomes were measured at the end of the 8-week intervention and after 24 weeks of unsupervised follow-up. Results No adverse effects were attributed to ADF and 93% completed the 8-week ADF protocol. At 8 weeks, ADF achieved a 376 kcal/day greater energy deficit, however there were no significant between-group differences in change in weight (mean±SE; ADF -8.2±0.9 kg, CR -7.1±1.0 kg), body composition, lipids, or Si. After 24 weeks of unsupervised follow-up, there were no significant differences in weight regain, however changes from baseline in % fat mass and lean mass were more favorable in ADF. Conclusions ADF is a safe and tolerable approach to weight loss. ADF produced similar changes in weight, body composition, lipids and Si at 8 weeks and did not appear to increase risk for weight regain 24 weeks after completing the intervention.

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with high fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild type or fructokinase knockout mice were fed a low fat (11%), high fat (36%) or high fat (36%) and high sucrose (30%) diet for 15 weeks. Both wild type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence for hepatic inflammation on a high fat diet compared to a low fat diet. In contrast, wild type mice fed a high fat and high sucrose diet developed more severe hepatic steatosis with low grade inflammation and fibrosis, as noted by increased CD68, TNF-alpha, MCP-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. Conclusion An additive effect of high fat and high sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis (NASH).

Skeletal muscle GLUT-4 transcription in response to treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), a known activator of AMP-activated protein kinase (AMPK), was studied in rats and mice. The increase in GLUT-4 mRNA levels in response to a single subcutaneous injection of AICAR, peaked at 13 h in white and red quadriceps muscles but not in the soleus muscle. The mRNA level of chloramphenicol acyltransferase reporter gene which is driven by 1,154 or 895 bp of the human GLUT-4 proximal promoter was increased in AICAR-treated transgenic mice, demonstrating the transcriptional upregulation of the GLUT-4 gene by AICAR. However, this induction of transcription was not apparent with 730 bp of the promoter. In addition, nuclear extracts from AICAR-treated mice bound to the consensus sequence of myocyte enhancer factor-2 (from -473 to -464) to a greater extent than from saline-injected mice. Thus AMP-activated protein kinase activation by AICAR increases GLUT-4 transcription by a mechanism that requires response elements within 895 bp of human GLUT-4 proximal promoter and that may be cooperatively mediated by myocyte enhancer factor-2.