The prevention of weight regain has emerged as the most significant obstacle in combating the obesity epidemic. Extensive research has shown that, when performed late in life, food restriction usually provides only a transitory solution and subjects quickly return to their “baseline” body weight soon after termination of the diet regimen. Such is the case for Sprague-Dawley DIO rats (Levin & Dunn-Meynell, 2000
) and obesity-prone and obesity-resistant Wistar rats (MacLean et al., 2004
). The study of adult animals has led to results showing that the energy gap increases with time in the weight reduced state (MacLean et al., 2004
), dispelling the hopes that the metabolic drive to regain weight may eventually dissipate if intake could be restricted long enough for the homeostatic system to readjust (MacLean et al., 2006
When chronically food restricted, OLETF males showed a marked normalization in plasma leptin, oxytocin and adiposity that was related to a reduction in fat cell size. Moreover, chronic pair feeding even increased their relative fat cell number, normalizing them to LETO controls.
Pathogenic adipose tissue (malfunctioning of adipocytes) is associated with many of the common metabolic diseases, like type II diabetes, hypertension and dyslipidemia, all of them present in the obese OLETF male (reviewed by Moran, 2008
). If adipogenesis is impaired during positive caloric balance, then existing adipocytes must undergo hypertrophy in order to store the excessive energy. Adipocyte hypertrophy may then be a result of the failure of adipocytes to adequately proliferate (Bays et al., 2008
). Since the enlargement of adipocytes is associated with substantial changes in metabolic functions (such as leptin- and insulin-resistance), it has been hypothesized that such alterations may contribute to the health risks of obesity. Alterations in adipocyte function have been reported in adult OLETF males in regard to their diabetes, and interestingly, caloric restriction improved their situation (Park et al., 2005
). Fat cells release a variety of adipokines and many other biologically active molecules (Ailhaud, 2006
) which may be involved in the development of a chronic low-grade inflammatory state that may, in turn, underlie the pathogenesis of the metabolic and cardiovascular complications of obesity. Large fat cells secrete higher amounts of adipokines such as leptin, IL-6, IL-8, TNF-alpha and adiponectin (among others), compared to small cells (Skurk et al., 2007
). In contrast to the increase in adipose cell size in obesity, obese subjects tend to have fewer of adipocytes (Gustafson et al., 2009
; Isakson et al., 2009
) and the amount of pre-adipocytes that can undergo differentiation is reduced in hypertrophic obesity (Isakson et al., 2009
; Permana et al., 2004
). Moreover, the capacity of pre-adipocytes to differentiate to adipose cells appears to be negatively correlated with both BMI and adipocyte cell size (Isakson et al., 2009
The adipocyte profile we found in free-feeding OLETF males is similar to the one described above. OLETF males develop adipocyte hypertrophy early in life, with a significant reduction in the relative amount of cell number (Schroeder, et al., 2009a
). While early
pair feeding successfully reduced cell size in the long term, it was the chronic
manipulation that in addition to cell size reduction also normalized the relative number of adipocytes to those of LETO controls. This combination of changes may imply an improvement in fat cell functioning that may be related to the improvement in diabetes reported by Park et al (2005)
Food restriction is associated with suppressed thermogenesis in brown adipose tissue and increased metabolic efficiency. Relative BAT weight (Rodriguez-Cuenca et al., 2002
) and UCP1 content are reduced in animals under food restriction, probably indicating a decrease in BAT thermogenic activity (Rothwell & Stock, 1982
; Valle et al., 2005
). Thus, the reduced energy expenditure which occurs during food restriction may be partly related to a lower activity of brown adipose tissue (Rothwell & Stock, 1982
). In adult pre-diabetic OLETF males, UCP1 (regulator of thermogenesis and body composition) and UCP3 are spontaneously reduced (Ryu et al., 2003
). This may cause diminished energy dissipation that could contribute to the development of obesity. Unfortunately, under chronic food restriction UCP1 and UCP3 are reduced even further in OLETF males (Ryu et al., 2003
). Similarly, in the present study, we found a significant reduction in BAT mass in chronic
pair feeding. In addition, toward the end of the chronic
pair feeding period, the feeding efficiency decreased significantly, showing that even if there is reduced energy dissipation by the BAT, OLETF males are not able to maintain their trajectory of weight gain (see ). This profile was not observed in the early
PF group. Thus, chronic pair feeding does not correct the OLETF pathology in this regard; it even appears to worsen the situation. In the early
pair fed animals the amount of BAT was not altered on PND90 compared to free-feeding OLETF rats. Overall, both of our manipulations seem to have had little (or even negative) effect on OLETF BAT mass (and hypothetically also function).
Oxytocin neurons in the PVN play a role in coordinating feeding termination (Blevins et al., 2003
; Olson et al., 1991a
; Verbalis et al., 1993
) by acting as targets for factors which induce anorexigenic behavior such as CCK (Olson et al., 1992
) and leptin (Hakansson et al., 1998
; Ur et al., 2002
). Central and peripheral concentrations of oxytocin are related and both are elevated in pathological states of energy balance such as obesity (Smith, 2006
; Stock et al., 1989
). One study further reported that oxytocin levels decreased significantly following gastric banding, a procedure that induced weight loss in the patients (Stock et al., 1989
). Accordingly, chronic
pair feeding in our model normalized plasma oxytocin (and leptin) to LETO controls.
The findings related to body weight and adipose tissue appear very promising, and while only the chronic manipulation achieved a normalized (to LETO) profile, early pair feeding produced significant long lasting effects on obesity levels that may imply perdurable improvements in the animals’ health. It was somewhat disappointing that the long term improvements just mentioned were not reflected by leptin and oxytocin levels at Day 90. The most promising result of this short-term manipulation was the reduction in voluntary intake observed in this group, which may suggest reorganization of central pathways implicated in energy regulation. If this is the case, this long term reduction in intake may lead to future reductions in adiposity and leptin and oxytocin levels that may improve long term health.
The present study provides further insights into the peripheral mechanisms underlying adiposity related adaptations in response to chronic
pair feeding in OLETF males. While chronic
pair feeding leads to an effective normalization of almost all the examined obesity parameters, such a prolonged food restriction is unlikely to be achieved in human subjects. Moreover, the reduction in plasma creatinine (though not significant) suggests a strong reduction in lean body mass that could be difficult to recover. On the other hand, the early
manipulation appears as a promising option for long term obesity reduction. A more moderate food restriction for a longer period of time or even the combination of it with exercise (which by itself successfully moderates long term obesity (Bi et al., 2005
) during childhood may provide long term results that cannot be achieved once the central and peripheral systems related to energy balance are mature and can hardly be modified.
Understanding the peripheral mechanisms by which adiposity is reconstituted after weight loss should be of high priority since it may lead to new ways of treating obesity and its associated metabolic complications. By extensively characterizing this model of weight regain, we may be able to use it to identify nutritional, behavioral, and pharmacological strategies that could counter the propensity to regain weight and would hopefully facilitate long-term weight reduction in obese and overweight subjects.