as obesity is becoming increasingly more prevalent in the united states , weight loss to reduce adipose tissue mass is strongly promoted as a means to decrease the disease risk associated with excess adiposity ( 5 , 57 ) .
unfortunately , the majority of individuals who lose weight are unlikely to maintain the reduced weight for an extended period of time ( 15 , 51 , 59 ) . repeated periods of weight loss and regain form a pattern known as weight cycling . hill ( 2004 ) indicates that popular and lay literature have asserted that weight cycling ( i.e.  yo - yo dieting  ) may increase the risk of developing cardiovascular disease or type ii diabetes to a greater extent than remaining weight stable at an obese body mass index ( bmi ; 30 kg / m)(27 ) .
because there is no universally - accepted definition of weight cycling , differences in experimental design may have contributed to discrepancies in scientific outcomes .
weight gain has significant implications concerning disease risk , which is believed to be mediated by an elevated level of systemic inflammation .
low - grade systemic inflammation is associated with obesity and it may serve as a link between adiposity and the development of cardiovascular disease and type 2 diabetes ( 66 ) . to our knowledge ,
discerning a difference in disease risk between maintenance of obesity and weight cycling is important and may provide insight concerning individual differences in disease progression .
if weight cycling is associated with an increased disease risk , continually recommending weight loss to those unable to maintain reduced weights may be a major public health issue .
this review has two aims : 1 ) to compare studies that both support or refute the theory that weight cycling is independently associated with increases in disease risk2 ) to discuss the possibility that weight cycling impacts pro - inflammatory biomarkers .
it has been estimated 24% of american men and 38% of women are currently attempting to lose weight ( 35 , 53 , 64 ) .
when individuals with an obese bmi are considered , 65% of men and 68% of women are trying to lose weight , which is a fivefold increase compared to those within the normal bmi ( 1824.9
while successful weight loss is achieved , researchers have indicated that long - term maintenance of a reduced weight appears to be rare . the probability of weight regain increases in the time following initial weight loss ( 43 ) .
researchers believe this is due to the energy gap created during caloric restriction where decreased energy expenditure is paired with an increased drive to eat ( 43 ) .
rodent studies have demonstrated that this gap persists regardless of the duration of weight reduction , which increases the probability of weight regain.(41 ) .
this drive to eat causes a hyperphagic response when free access to food is allowed and when paired with suppressed lipid utilization , weight regain is often rapid and efficient ( 41 , 43 ) .
while this finding was elucidated through use of a rodent model , human weight regain data supports this concept .
one year after a modest weight loss ( 14.5% of body weight ) , votruba et al .
( 2002 ) reported that within a year of weight loss , 16 out of 28 women regained weight and had a 19% increase in body weight and a 26% increase in percent fat mass ( 59 ) .
weiss reported that by one year after a modest weight loss ( 10% of body weight ) , 33% of adult subjects regained all lost weight .
furthermore , they concluded that the odds of regaining were positively associated with the percentage of initial weight lost ( 63 ) .
field et al . reported that approximately 55% of overweight and obese women who lost 10% of their body weight regained all lost weight within 4 years ( 15 ) . in support of this finding ,
within 9 years of the initial weight loss ( 5% of body weight ) , 95% of women and 93% of men were unable to maintain the reduced body weight(51 ) .
collectively , these studies suggest that while initial weight loss is possible , long - term maintenance is problematic , especially when large amounts of weight are lost or an individual is overweight or obese .
repeated bouts of weight loss followed by regain forms a pattern known as weight cycling .
survey data collected by williamson and colleagues ( 64 ) indicated that 25% of men and 27% of women trying to lose weight have made long - term attempts ( classified as trying for over 1 year or  always trying to lose weight  ) .
it has also been shown that 7% of men and 10% of women can be classified as severe weight cyclers ( intentionally lost at least 5 kg and regained at least three different times ) , while 11% of men and 19% of women are mild weight cyclers ( lost and regained at least 5 kg on one or two occasions ) ( 36 ) . while these results were generated from a group of adults in finland , the conclusion that 18% of men and 27% of women weight cycle is comparable to the prevalence described by williamson et al .
these numbers are likely a conservative estimate of the prevalence of weight cycling , which may be even greater in the united states .
the physiological changes associated with weight cycling , such as energy expenditure , metabolism and fuel utilization , have been documented using a rat model .
maclean and colleagues ( 2004 ) have documented the physiological alterations occurring in obesity - prone rats that contribute to the rapid , efficient regain during relapse following weight loss and maintenance .
their focus has been on the energy gap created during a period of caloric restriction that is characterized by decreased energy expenditure and an increased drive to eat ( 42 ) .
they found that in addition to changes in energy intake , alterations in metabolic efficiency and fuel utilization ( favoring carbohydrate oxidation ) may significantly affect the propensity to regain weight ( 43 ) .
for instance , in the 16 weeks following moderate weight loss ( 14% ) , food efficiency was increased 10-fold upon the first day of a 56-day re - feeding in weight cycle rats compared to rats with established obesity . while this dramatic rise was reduced within several days , food efficiency remained elevated above levels in obese mice for the first 4 weeks of relapse ( 41 ) .
the most dramatic changes occurred during the first week of relapse , a time when nearly 40% of lost weight , which was primarily fat mass , was regained ( 41 , 42 ) .
researchers also noted that as the length of maintenance increased , the amount of weight regained upon relapse also increased .
furthermore , regain was accompanied by a 30% increase in adipocyte concentration per fat pad .
based on the above literature , it is clear that weight gain during relapse appears to induce more rapid adipose tissue growth and hyperplasia due to metabolic shifts favoring lipid storage .
because adipose tissue is a metabolically active tissue , responsible for production of leptin , cytokines and adiponectin as well as responding to traditional hormone systems(32 ) , it is possible that the consequences of weight gain during relapse may also differ from that of initial weight gain . in recent years , lay literature has asserted that weight cycling may be more detrimental to health than simply remaining overweight or obese ( 27 , 30 ) .
researchers have found associations between weight cycling and an overshoot of lipogenic enzyme , triglyceride and cholesterol levels in animals and increased risk of heart attack and stroke in humans ( 4 , 16 , 34 , 52 ) . however , other researchers noted no long term adverse effects on body composition , blood pressure , lipid profile or risk of developing type ii diabetes ( 13 , 22 , 37 , 49 , 56 ) . due to limited research in the area of weight cycling all of the negative consequences may not be known .
existing studies differ considerably in their research design , subject population used , duration of treatment , incorporation of exercise , magnitude and frequency of weight cycles .
the lack of a universal definition of weight cycling is perhaps a great contributor to the variability within experimental design .
this variability is discussed in greater detail in the following sections . according to published research ,
weight cycling has been evaluated in one of two main ways : using a cross - sectional survey model in humans or a longitudinal endpoint model in rodents .
the next two sections highlight research that either support or refute the theory that weight cycling contributes to detriments in health , demonstrating the no definite conclusions can be reached at this time .
utilization of animal experimental models allows for more control of subject treatment than a human experimental model .
such designs are useful for examining mechanisms underlying weight cycling ; however , care should be taken when translating these findings to humans .
an increase in internal validity , resulting from more control of subject treatments may explain why reported conclusions regarding weight cycling in animals is a bit more consistent than humans .
the most likely explanation for inconsistent findings is due to the manner in which the weight cycling response is elicited . in agreement with the series of studies completed by maclean et al .
, rapid regain occurs during relapse in rats that have been on caloric restriction diets ( 6 , 17 , 26 , 28 ) .
weight cycling was associated with increased food efficiency ( 6 , 50 ) and increased caloric consumption ( 26 , 52 ) .
found that despite being at lower weights than control rats , weight cycled rats were significantly fatter(50 ) .
reported that weight cycled rats had a lower percentage of fat free mass than their free fed ( high fat diet ) counterparts and that amount of weight lost during period of restriction decreased with each successive cycle ( 28 ) . during re - feeding periods in weight cycled rats ,
researchers have consistently reported overshoots in lipoprotein lipase , serum triglycerides , and serum cholesterol above what has been observed in rats that are free - fed a high fat diet ( 17 , 34 , 52 ) .
it has been speculated that body weight overshoot may create a state of hyperlipogenesis that may persist for several days after re - feeding .
kim et al . demonstrated that fasting serum leptin was significantly increased in weight cycled rats compared to lean and pair - fed controls despite similar quantities of fat mass(33 ) .
since leptin concentration is highly correlated to the degree of adiposity ( 11 , 39 ) , further interpretation of this finding suggests that weight cycling may induce a physiological change in adipocyte release of leptin .
in contrast , brownell et al . did not observe alterations in body composition , but this could be contributed to an experimental design that only allowed weight cycled rats to regain weight until they matched their obese controls , even though weight gain was still persisting at that time ( 6 ) . also , cleary et al .
indicated that weight loss and weight regain were linear in nature , opposing the  energy gap  theory proposed by maclean et al .
however , rats in the cleary model were fed a purified diet rather than a high fat diet ; the purified diet contained 20.5% high nitrogen casein , 50% cornstarch , 5% sucrose and 5% corn oil with 9% celufil as a filler ( 9 ) .
demonstrated that re - feeding rats a moderate fat ( 22% ) diet yielded blunted responses compared to those fed a high fat ( 45% ) diet ( 52 ) .
furthermore , given a choice , weight cycled rats have been shown to self - select diets with high fat content during re - feeding(50 ) , so perhaps a purified diet was not an appropriate variable for re - creating the weight cycling experience .
gray et al . stated that the rate of each weight loss was not hindered by weight cycling(23 ) ; however , in this study , the first restriction was marked by a 50% reduction of intake and the second restriction was a 75% reduction , so perhaps weight loss would not have been similar between weight cycles had the second restriction not have been so severe .
kim et al.(33 ) were not able to demonstrate a hyperphagic response , but their use of a 24hr fast plus 24hr relapse for 21 cycles may not have been a design that could show effects of weight cycling seen in previously mentioned studies ; every - other - day restriction has lead to other positive adaptations ( less weight gain , increased insulin sensitivity ) elsewhere ( 1 ) .
this may indicate that larger weight cycles ( increased weight loss frequency / magnitude per cycle ) have differing effects as suggested by weight cycling studies in humans .
some existing scientific literature supports the theory that weight cycling increases disease risk ( directly or indirectly ) in humans .
wallner and colleagues found that a history of weight cycling was associated with a more pronounced android fat distribution in women compared to those who were normal - weight or overweight without a history of weight cycling ( 60 ) .
it is possible that women who are prone to the accumulation of abdominal adiposity may be more likely to weight cycle for a more aesthetically desirable figure ( 48 ) .
regardless of whether weight cycling causes the accumulation of android adiposity or vice versa , other researchers have found that a history of weight cycling was independently associated with an increased risk of developing hypertension ( 24 ) and clinically significant decreases in hdl - cholesterol in women ( 47 ) .
french et al(16 ) and vergnaud et al.(58 ) demonstrated associations between weight cycling and risk for heart attack and stroke , as well as the development of metabolic syndrome(16 , 58 ) .
studied men enrolled in the multiple risk factor intervention trial who were at elevated risk for coronary heart disease due to smoking , hypertension and hypercholesterolemia , finding that greater weight variability over 4 years of follow up was associated to increase all - cause mortality(4 ) .
in contrast to the preceding reports , several other researchers reported that weight cycling has no independent impact on health status .
prentice et al . found that weight cycling did not significantly alter body composition ( 49 ) .
however , unlike wallner et al.(60 ) , who asked for 4 years worth of weight history , this study was completed in only 18 weeks .
it may be possible that any deleterious effects of weight cycling do not manifest immediately or that the magnitude of the weight loss was not sufficient to induce long - term change .
studied obese patients , in a multi - disciplinary weight loss program , who had relapsed and re - entered .
multiple attempts at weight loss over 12 years showed no effect on the rate at which weight could be lost each time or on blood pressure or lipid profile ; in fact , these measurements at baseline were significantly lower at the time of re - entry compared to the initial start for men and women ( 37 ) .
initial blood pressure in men ( 134/88 mmhg ) and women ( 126/82 mmhg ) was recorded at the restart baseline at 129/85 mmhg and 121/78 mmhg , respectively . while no subjects were hypertensive
mmol / l between initial and restart baselines and cholesterol was reduced by 0.1 and 0.5
women s values were all within the normal / low risk range and men s values remained in the borderline high range .
cholesterol values for both genders were all in the borderline high risk range . while deemed statistically significant , the differences between baselines may not be physiologically relevant as disease risk did not appear to change .
even though this study was longitudinal in nature , perhaps the use of regular exercise as part of the program acted as a confounding factor , as aerobic exercise is independently and positively correlated with decreases in blood pressure and cholesterol ( 19 , 25 ) .
a similar exercise effect was reported by field et al . where mild and severe weight cycling was strongly associated with weight gain and hypertension , controlling the statistical analysis for weight and weight
gain greatly attenuated this correlation(13 ) ; however , the questionnaire data also revealed that severe weight cyclers exercised significantly more that non weight cyclers .
( 2004 ) noted that weight cycling had no effect on cardiovascular disease risk factors ; weight cycling throughout adulthood was not associated with changes in body composition , fat distribution blood pressure or insulin levels(22 ) .
one major difference in this study , compared to those with competing findings , was that graci et al.(22 ) used morbidly obese subjects ( bmi up to 69 kg / m ) and perhaps there is a less - pronounced response to weight cycling in this population because the subjects already have an elevated disease risk .
( 65 ) and jeffery et al.(31 ) may have been effected by the short duration of measurement period ( 2.5 years ) or the failure to use appropriate blood pressure cuffs for obese patients(24 ) .
field et al . concluded that 4 years of weight cycling , prior to diagnosis of type 2 diabetes , was not predictive of disease development while wannamethee et al found that weight fluctuation does not directly increase risk of death ( 14 , 61 ) .
when differences in experimental design are accounted for , a significant gap in scientific knowledge exists concerning the exact role of weight cycling in the progression of chronic diseases that are normally attributed to excess adiposity .
il-6 stimulates hepatic release of acute phase proteins , including c - reactive protein ( crp ) ( 3 , 66 ) .
free fatty acids and tnf- act in concert to exacerbate systemic inflammation ( 54 ) .
il-8 , released from adipocytes , monocytes and macrophages , has been thought to induce chemotaxis helping to form atherosclerotic plaques(21 ) . il-6 and tnf- can act in an autocrine or paracrine manner , impairing insulin receptor activity and glucose sensitivity in adipocytes and muscle tissue ( 2 , 3 , 45 , 66 ) .
il-6 and crp in circulation target and damage arterial endothelial lining ; this damage helps to initiate or progress atherosclerosis ( 3 , 46 , 66 ) .
several mechanisms are responsible for the pro - inflammatory response in adipose tissue due to hypertrophy .
cytotoxic stressors , such as oxidative stress and hypoxia , induced by hypertrophy in adipose tissue have been reported to trigger subsequent pro - inflammatory events ( 18 , 55 ) . as cellular stress persists ,
adipocytes secrete il-6 , tnf- and leptin ( 38 , 55 ) and unless revascularization is adequate , cells may become necrotic ( 44 ) .
the level of necrotic adipocyte death is positively correlated with increased adiposity and concentration of resident macrophages ( 8) .
leptin aids in the transmigration of blood monocytes into adipose tissue compartments , where they mature into macrophages ( 12 ) .
also , leptin stimulates pre - adipocyte stem cells to mature into adipocytes or macrophages .
thus , an adiposity driven increase in adipose tissue macrophages concentration is a result of monocyte influx and directed pre - adipocyte transformation ( 7 ) .
evidence exists that macrophages may be retained longer in adipose tissue from obese compared to lean subjects ( 40 ) . in lean individuals , the actions of leptin and granulocyte macrophage 
colony stimulating factor ( gm - csf ) are opposed by ghrelin ; however , reduced ghrelin in obese individuals causes deregulation of macrophage development in adipose tissue ( 20 ) .
macrophage accumulation has significant implications for inflammatory disease risk because they are a significant source of il-6 , tnf- , and il-8 ( 62 , 67 ) .
to our knowledge , there is only one published study that examined the effect weight variability has on pro - inflammatory or related factors .
reported that japanese men with a history of weight variability had an independently increased odds ratio of elevated crp ( 68 ) .
one limitation of this study was that it was a cross - sectional design thus it was not possible to evaluate cause and effect , no information on intentionality of weight change and the cross - sectional design with a majority of subjects having final bmis less than 25 kg / m .
this lack of literature suggests that in order to fully understand the possible effects of weight cycling , we must include examination of pro - inflammatory responses to this pattern .
in recent years , lay and popular literature has claimed that weight cycling may be more detrimental that simply remaining overweight or obese .
scientific research has yielded mixed results , but this may be due to differences in population used , experimental design and method of weight cycling . a current gap in research is the pro - inflammatory effect of weight cycling .. since obesity is so prevalent , weight loss is almost universally recommended as treatment to reduce disease risk . but because research indicated that relapse is likely , it is important to understand if weight cycling adds to the current disease risk of obesity . because weight cycling has a distinct effect on adipose tissue and adipose tissue is a source of inflammatory cytokines ,
elucidating any increases in inflammation beyond that measured in sustained obesity may help us to understand the independent disease risk that can be associated with weight cycling .
 research indicates that weight cycling , or  yo - yo dieting  is a common occurrence in overweight and obese populations . 
 the long term negative health consequences of weight cycling are debated and it is unclear whether or not this weight change pattern poses a greater disease risk compared to obesity maintenance . 
 this review discusses the prevalence of weight cycling and physiological alterations occurring during weight loss that promotes weight regain . 
 we also discuss the effect weight regain has upon adipose tissue in terms of rate and type of accumulation . also within this review 
 are discussions surrounding the previously published literature based upon human and rodent research . 
 we focus on previous limitations and difference in experimental design that have perhaps resulted in mixed findings concerning independent effects of weight cycling on health parameters . 
 the final purpose of this review is to discuss future directions in evaluating the pro - inflammatory response to weight cycling in order to compare the disease risk compared to obesity maintenance . 
Overview of the Problem
Weight Cycling: A Disruption of Body Weight Maintenance?
Does Weight Regain Disrupt Normal Physiology?
Longitudinal Endpoint Analysis of Weight Cycling: Rodent Models
Cross-sectional Evaluation of Weight Cycling: Human Models
Role of Inflammation in Disease Progression: Implications for Weight Cycling
Summary