Adaptive thermogenesis driving catch-up fat during weight regain: a role for skeletal muscle hypothyroidism and a risk for sarcopenic obesity

Abstract

Across the spectrum of weight regain, ranging from cachexia rehabilitation and catch-up growth to obesity relapse, the recovery rate of body fat is often disproportionate relative to lean tissue recovery. Such preferential ‘catch-up fat’ is in part attributed to an increase in metabolic efficiency and embodied in the concept that ‘metabolic adaptation’ or ‘adaptive thermogenesis’ in response to large weight deficits can persist during weight regain to accelerate fat stores recovery. This paper reviews the evidence in humans for the existence of this thrifty metabolism driving catch-up fat within the framework of a feedback loop between fat stores depletion and suppressed thermogenesis. The search for its effector mechanisms suggests that whereas adaptive thermogenesis during weight loss results primarily from central suppression of sympathetic nervous system and hypothalamic-pituitary-thyroid axis, its persistence during weight regain for accelerating fat recovery is primarily mediated through peripheral tissue resistance to the actions of this systemic neurohormonal network. Emerging evidence linking it to an upregulation of skeletal muscle type 3 deiodinase (D3), the main thyroid hormone inactivating enzyme, along with slowed muscle metabolism and altered contractile properties, suggest that D3-induced muscle hypothyroidism is a key feature of such peripheral resistance. These findings underlying a role of skeletal muscle hypothyroidism in adaptive thermogenesis driving catch-up fat, but which can also concomitantly compromise muscle functionality, have been integrated into a mechanistic framework to explain how weight cycling and large weight fluctuations across the lifespan can predispose to sarcopenic obesity.

Introduction

Obesity, which is defined by the World Health Organization as an ‘abnormal or excessive fat accumulation that presents a risk to health’ [1], is now increasingly referred to as a ‘chronic relapsing disease process’ [2–4]. Its characterization as a ‘disease process’ highlights the multitude of pathways by which excess adiposity can contribute to the pathogenesis of chronic debilitating diseases (i.e. type 2 diabetes, cardiovascular and musculoskeletal diseases, several types of cancer) [5–7], while its ‘chronic relapsing’ nature underscores the existence of a body weight set point or settling point that is defended [8]. In other words, the physiological response to weight loss in people with obesity, just as in those who are lean, triggers compensatory mechanisms for weight regain [9–11].

In many situations of weight regain across the lifespan, however, body fat seems to be prioritized in that there is a disproportionately faster recovery of fat mass, with lean tissue recovery lagging behind. This phenomenon, coined as preferential ‘catch-up fat’ [12, 13], has been documented during controlled refeeding after experimental semistarvation in young men [14], during nutritional rehabilitation of malnourished adults and children [15–17], during catch-up growth after fetal or neonatal growth perturbations [13, 18–23], and during recovery from anorexia nervosa [24–27] or various pathophysiological hypermetabolic states that include cancer, septic shock, AIDS and COVID-19 [28–31]. It has also been observed during obesity relapse after substantial weight loss achieved by either lifestyle interventions (dieting and/or exercise) [32–34] or by bariatric surgery [35, 36].

The almost ubiquitous nature of this preferential catch-up fat phenomenon across the human lifespan, even under conditions of restricted refeeding or when refed well-balanced diets, suggests that an increased metabolic efficiency for fat recovery is a fundamental physiological process after substantial weight deficit. Its underlying mechanisms, however, remain poorly understood, amid considerable interests in this thrifty metabolism for catch-up fat as a contributing factor in the links between weight fluctuations and later chronic metabolic diseases [12, 13, 23]. The aims of this article are as follows:

1. to review the evidence in humans which suggest that such metabolic adaptation or adaptive thermogenesis in response to large weight deficits may persist during weight regain for the purpose of accelerating fat recovery or catch-up fat,

2. to substantiate the contention that the mechanisms underlying this thrifty catch-up fat phenotype, rather than resulting from central suppression of the neurohormonal network that control thermogenesis, is primarily mediated through peripheral resistance to the actions of this neuro-hormonal network; so far characterized by alterations in the local metabolism of thyroid hormones in skeletal muscle, and,

3. to integrate this state of skeletal muscle hypothyroidism driving the thrifty catch-up fat phenotype into a mechanistic framework to explain how weight cycling and large fluctuations in body weight across lifespan can predispose to sarcopenic obesity; the latter being defined as the co-existence of excess adiposity and low skeletal muscle mass and/or functions [37].

Adaptive thermogenesis during weight loss

The notion that humans and other mammals respond to energy deficit by conserving energy through regulated heat production has a long (century old) history. Its origin in humans can be traced to Francis Benedict’s experiments of prolonged fasting during which the basal metabolic rate was found to fall at a disproportionately greater rate than that of body weight [38]. It was several decades later that this notion of energy conservation gained recognition, notably when Ancel Keys and colleagues quantified the marked reduction in basal metabolic rate beyond that explained by reduced ‘metabolically-active mass’ in young men participating in the classic Minnesota Starvation Experiment [14]. The concept of energy conservation by regulated heat production was subsequently extended to therapeutic dieting in the late 1960’s when George Bray showed a disproportionate fall in basal metabolic rate relative to weight loss during caloric restriction in patients with severe obesity [39]. He concluded, to quote: ‘These seem to support the concept that the body can adapt to caloric restriction by decreasing its energy needs and by becoming metabolically more efficient. These changes partially offset the expected weight-loss.’ [39]. This concept of energy conservation counteracting therapeutic weight loss was reinforced a decade later by Miller and Parsonage [40] who investigated the energy expenditure (EE) of women who were isolated in a country house and fed 1500 kcal daily for 3 weeks. They found that several of them showed resistance to slimming which was characterized by a low basal metabolic rate and daily EE, and concluded that they have become ‘metabolically adapted to a low-energy diet’. Since then, metabolic adaptation resulting from regulatory or adaptive thermogenesis in response to weight loss has been well documented in both resting and non-resting components of daily EE [41–44].

Adaptive thermogenesis, most often assessed as basal metabolic rate or resting EE (REE) that is lower than that predicted from changes in fat-free mass (FFM) and fat mass, has been demonstrated after experimentally-induced severe or modest energy deficit in healthy young adults of normal body weight [14, 45–47], in patients with anorexia nervosa [26, 48, 49], after weight loss in athletes [50, 51] and in healthy older individuals [52–55], as well as after therapeutic slimming by dieting and/or exercise in young and older people with overweight or obesity [55–59]. It has also been observed in some studies of weight loss induced by bariatric surgery in patients with morbid obesity [60] and after novel pharmacological therapy with GLP1 analogues [61, 62]. Adaptive thermogenesis in the non-resting component of daily EE has also been demonstrated after weight loss induced by lifestyle interventions, namely when assessed as diminished energy cost of exercise after weight reduction [63–67] or as diminished movement-associated thermogenesis characterized by a reduction in spontaneous physical activity [68]. Notably, in their weight-clamping experiment to demonstrate adaptive changes in daily EE with body weight clamped at 10% or 20% below habitual weight maintenance, Leibel et al. [69] calculated that most (> two-thirds) of adaptive thermogenesis occurred in the non-resting component of daily EE, and which for most subjects corresponded to an energy sparing of ~ 150 to 250 kcal/day. There is also some evidence that adaptive thermogenesis may persist for several months to several years in individuals successfully maintaining their lost weight [70–73], thereby underscoring its functional role in slowing the rate of weight loss and in reducing the energy requirement of the weight-reduced state.

Neurohormonal network

From a physiological standpoint, adaptive thermogenesis in response to energy deficit is primarily mediated through diminished activity of the sympathetic nervous system (SNS), together with depressed hypothalamic–pituitary–thyroid (HPT) axis which leads to diminished circulating levels of thyroid hormones [74–79]. Which organs/tissues are involved in such energy conservation are not well defined. Studies in laboratory rodents suggest the involvement of diminished brown adipose tissue thermogenesis via diminished SNS activation of its uncoupling protein (UCP1) [80, 81]. Several other organs and tissues are probably involved as measurements of regional blood flow coupled with arterio-venous oxygen consumption in the rat suggest that quantitative important energy savings occur in splanchic organs and musculo-skeletal mass in response to starvation [82]; the molecular effectors involved, however, remain elusive. Following the realization that the uncoupling protein homologues UCP2 and UCP3, which are highly expressed in skeletal muscle, are unlikely to be physiologically relevant uncoupling proteins that mediate thermogenesis in response to diet and cold [81], there has been renewed interest into ‘futile’ cycles which, through increased utilization of ATP by ion pumps and substrate cycles, could participate in the control of skeletal muscle thermogenesis. Those that have generated the most interests include glycolytic substrate cycles [83, 84], protein turnover [85], the triglyceride hydrolysis/re-esterification cycle [86], substrate cycling between de-novo lipid synthesis and beta-oxidation [87], and calcium cycling which is mediated by the sarco/endoplasmic reticulum Ca²⁺-ATPase pump and its modulator sarcolipin [88]. To date, however, there is no direct evidence that their downregulation leads to quantitatively important energy conservation following weight loss. Nonetheless, several studies in humans suggest a role for diminished skeletal muscle thermogenesis, as judged by an increase in muscle work efficiency after weight loss [63, 64, 65, 66, 67, 89–90], which in some of these studies could be associated with increased gene expression of the more efficient molecular isoforms of myosin heavy chain and sarco/endoplasmic reticulum Ca²⁺-dependent ATPase, namely MHC-1 and SERCA-2 [89, 90]. Overall, these changes in skeletal muscle metabolism could be consequential to the depressed neuroendocrine network (SNS and HPT axis) resulting from diminished secretion of insulin and leptin in response to energy deficits.

Kinetics

In fact, it is generally accepted that in response to caloric restriction, there is an early and prompt reduction in REE [46, 91] which is triggered by the impact of the rapid fall in insulin and leptin secretions on central activation of SNS outflow and HPT axis [75, 92–97]. In their study investigating the kinetics of REE and body composition changes during the course of caloric restriction in young men, Müller et al. [46] showed that adaptive thermogenesis in REE became significant as from day 3, associated with a significant drop in circulating insulin on day 3 and leptin by day 7, and that the magnitude of adaptive thermogenesis was maintained over the 3 week study period of caloric restriction [46]. In longer term caloric restriction studies, however, the magnitude of adaptive thermogenesis in REE was found to increase over several months, both in lean subjects [14] and in patients with obesity [98]. While such a progressive fall in adaptive thermogenesis over months suggests that its magnitude is also determined by the severity of weight loss, the available evidence in humans losing weight after moderate-to-severe energy deficit suggests a specific link between adaptive thermogenesis and the degree of fat mass depletion, but not with FFM depletion [45, 58, 99–102]. Taken together, these above-mentioned studies suggest that following a major energy deficit, the adaptive reduction in thermogenesis is driven not only by an early and prompt reduction in EE in response to the energy deficit, but also by a slower decline in EE as the body’s fat stores are depleted.

Adaptive thermogenesis during weight regain

In contrast to strong evidence from studies in laboratory animals that adaptive thermogenesis persists during weight regain to enhance the efficiency of fat recovery [103–107], the evidence for its persistence during weight regain in humans are few. They can be derived from studies of weight regain after weight losses that ranged from substantial (10–15%) to severe (20–40%); these studies are summarized in Table 1 and outlined below; the term mass-adjusted EE referring to EE after adjusting for changes in FFM and fat mass.

Table 1.

Human investigations revealing metabolic adaptation (adaptive thermogenesis) persisting during partial weight regain

	Minnesota Experiment revisited	Biosphere 2 Experiment	Biggest Loser Competition Study	Kiel Study	CALERIE Study
Publications	Dulloo & Jacquet (1998) Ref.[45]	Weyer et al. (2000) Ref. [68]	Fothergill et al. (2016) Ref. [34]	Bosy-Westphal et al. (2013) Ref. [108]	Marlatt et al. (2017) Ref. [109]
Subjects men/women	n = 32 32/0	n = 8 4/4	n = 14 6/8	n = 27 6/21	n = 18 5/13
Age category	Young	Young	Young and middle-aged	Young	Young and middle-aged
Weight Status	Normal weight	Normal weight and Overweight	Class III obesity	Overweight and Obesity	Overweight
Intervention + follow-up	6 months semistarvation + 12 wk refeeding	2 years food insufficiency + 6 month follow-up	30 wks dieting & exercise + 6 year follow-up	13 wks low-calorie diet + 6 month follow-up	2 years caloric restriction + 2 year follow-up
Weight lost (% baseline)	− 24%	− 14%	− 39%	− 10%	-12%
Recovery (% lost) 1,2 or Regained (kg)3
• Weight  • FM  • FFM	33% 44% 28%	8.8 kg 8.4 kg 0.4 kg	70% 75% 52%	70% 60% n/a	54% 33% n/a
Metabolic adaptation (kcal/d)4
• Wt loss  • Wt regain	− 408 − 166	− 120 − 129	− 275 − 499	− 93 -103	− 91 − 91
Thyroid hormone5, 6 (relative to baseline or controls = 1)
• Wt loss  • Wt regain	-	0.93 1.26	0.56 1.19	0.93 0.92	-

¹ Wt = weight; FM = Fat mass; FFM = Fat-free mass

² For two of these studies [108, 109], FFM recovery is indicated as ‘n/a’ (not applicable) as there was no significant loss in FFM during weight loss

³ For the Biosphere study, as body composition was not assessed before entry to confinement, data are presented as kg ‘regained’ between exit from confinement and 6 months later

⁴ Metabolic adaptation (kcal/d) is calculated from change in energy expenditure (EE) adjusted for changes in FFM and FM

⁵ Thyroid hormone refers to circulating levels of free triiodothyronine (T3); (-): data not available

⁶ For the Biosphere study [68], because thyroid hormones were not measured before entry, values 15 months after exit were used as a retrospective control

1. The Minnesota Starvation Experiment Revisited [45] refers to the reanalysis of data on changes in basal metabolic rate and body composition in 32 young men volunteers in the normal range of body mass index (BMI) who on average lost 24% of body weight over 6 months on a semistarvation diet. Adaptive thermogenesis, assessed as a reduction in mass-adjusted REE during weight loss, was found to be still present (albeit attenuated) after 12 weeks of restricted refeeding - a time point at which body fat recovery (kg of fat regained as % of kg of fat loss) was nearly 50% compared to only 30% for FFM recovery.

2. The Biosphere 2 Experiment [68] refers to an investigation of 8 adults of normal or overweight BMI who had lost about 14% of their body weight because of sustained food insufficiency after a 2 year confinement in a self-contained ecologic “miniworld” and prototype planetary habitat. Adaptive thermogenesis, assessed as lower mass-adjusted 24 h EE and sleep EE, as well as lower spontaneous physical activity relative to a control group, was observed within a week after exit of the Biosphere confinement, and to persist 6 months later despite regaining most of the lost weight (8.8 kg), which comprised essentially of body fat (+ 8.4 kg).

3. The Biggest Loser Competition Study [34] is based on a nationally televised U.S. weight loss competition among 14 participants with severe (class III) obesity who lost about 40% of their body weight over 30 weeks of a weight loss program consisting of diet restriction and high-intensity exercise. Adaptive thermogenesis assessed as mass-adjusted REE) at the end of the weight loss period was found to persist 6 years after the competition ended, by which time they had recovered 70% of their lost body weight, with body fat recovery being 75% compared to 52% for FFM recovery.

4. The Kiel Study [108] and the CALERIE Study [109] refer to two lifestyle intervention studies in which people with overweight or obesity lost about 10% of body weight, but without losing a significant amount of FFM. In the Kiel study, adaptive thermogenesis (assessed as REE adjusted for changes in organ and tissue masses) after weight loss remained diminished after partial weight recovery 6 months later, while in the CALERIE study, adaptive thermogenesis assessed as diminished mass-adjusted sleep EE was also found to persist two years later after partial weight recovery.

These studies revealing persistent adaptive thermogenesis linked specifically to an accelerated recovery of body fat during weight regain, together with other studies showing associations between reductions in mass-adjusted EE and the loss of fat mass (but not loss of FFM) during weight loss by caloric restriction and/or exercise [45, 58, 99–102], suggest the existence of a feedback-loop between adaptive thermogenesis and the depletion of the fat stores. This contention is reinforced by other findings from the re-analysis of data from the Minnesota Starvation Experiment indicating a continuum, through both weight loss and subsequent weight regain, of a positive relationship between reduced mass-adjusted REE and the degree of fat depletion (but not with the degree of FFM depletion) [45]. It is also supported by a recent study of lifestyle intervention in postmenopausal women with overweight/obesity indicating that after weight loss, a low REE adjusted for changes in body composition predicted the regain of fat mass (but not that of FFM) two years later [110].

Collectively, these above-mentioned findings in humans, together with those from animal studies, are in support of the concept that there are two distinct control systems for adaptive thermogenesis in response to energy deficit [45, 111]: a rapid reacting system to the energy deficit per se, and a slow-reacting system to the fat stores depletion per se. The latter, which is referred to as an ‘adipose-specific’ control system and whose function is to accelerate fat restoration, is distinct from the ‘non-specific’ control system, which is viewed as a more rapid reaction system under the control of the SNS and HPT-axis, and whose function is to attenuate energy imbalance consequential to reduced food energy flux, thereby slowing the rate of weight loss and lowering the energy requirements for weight loss maintenance (Fig. 1).

Fig. 1.

Schematic representation of the two distinct control systems for adaptive thermogenesis underlying metabolic adaptation during prolonged energy deficit (starvation) and subsequent refeeding. One control system (blue line) is a direct function of changes in the food energy supply (green line). It responds relatively rapidly to the energy deficit, triggered by the rapid fall in insulin and leptin secretions and their consequential diminished central actions on sympathetic neural system (SNS) outflow and hypothalamic-pituitary-thyroid (HPT) axis controlling thermogenesis. Upon refeeding, this neuroendocrine network is restored relatively rapidly as a function of energy re-availability (levels 1–4) and may increase further, particularly if hyperphagia occurs during refeeding (level 4). Since the efferent limb of this control system (SNS activity and HPT axis) is influenced by overlapping or interacting signals arising from a variety of environmental stresses, including food deprivation, deficiency of essential nutrients, excess energy intake, and exposure to cold or to infections, it is therefore referred to as the “non-specific” control of thermogenesis, and is likely to occur primarily in organs/tissues with a high specific metabolic rate (e.g., liver, kidneys, brown adipose tissue). The other control system (red line), by contrast, is independent of the functional state of the aforementioned neurohormonal network. It has a much slower time constant by virtue of its response only to signal(s) arising only from the state of depletion/repletion of the fat stores. It is therefore referred to as the “adipose-specific” control of thermogenesis, and its energy sparing is postulated to result from peripheral resistance to the actions of the aforementioned systemic neuroendocrine network. The energy thus spared during weight regain is directed specifically at the replenishment of the fat stores, resulting in preferential catch-up fat [112]. Adapted from Dulloo and Jacquet [111]

Independency of neurohormonal network

During refeeding and weight regain, the rapid rise in insulin and leptin [75, 76, 78, 95] leads to restored activity of the SNS and HPT axis and hence reactivation of the ‘non-specific’ control of thermogenesis, leaving the sustained energy sparing for catch-up fat primarily under the control of ‘adipose-specific’ suppression of thermogenesis (Fig. 1). In fact, during partial weight regain characterized by preferential catch-up fat in both the Biggest Loser Competition Study [34] and in the Biosphere 2 Experiment [68], the persisting adaptive thermogenesis could still be demonstrated when the circulating level of the biologically active thyroid hormone 3,5,3′-triiodothyronine (T3) was no longer lower (but somewhat higher) than baseline or control levels (Table 1). Furthermore, the demonstration in the rat that the thrifty catch-up fat phenotype is observed across a wide range of ambient temperature (ranging from housing near thermoneutrality at 29 °C to cold exposure at 6 °C) provide strong evidence that the suppressed thermogenesis driving catch-up fat can occur independently of the sympathetic control of thermogenesis [113], and by extension independently of the functional state of brown adipose tissue UCP1 whose activity is primarily determined by the SNS [74, 80, 81]. Together, these findings reinforce the contention that the mechanisms driving the ‘adipose-specific’ suppression of thermogenesis can be dissociated from the systemic neuroendocrine network controlling thermogenesis, and that they operate in tissues other than brown adipose tissue to conserve energy for catch-up fat.

Adipose-muscle model

Instead, a feedback loop between the white adipose tissue fat stores depletion and skeletal muscle thermogenesis has been postulated [111], as illustrated in Fig. 2.

Fig. 2.

Adipose-Muscle model of a feedback loop between the adipose tissue fat stores and skeletal muscle thermogenesis comprising a sensor(s) of the state of depletion of the fat stores, a signal(s) dictating the suppression of thermogenesis as a function of the state of depletion of the fat stores and an effector system mediating adaptive thermogenesis in skeletal muscle. Following the onset of refeeding, the increase in insulin and leptin secretions re-activates central sympathetic nervous system (SNS) outflow and the hypothalamic-pituitary-thyroid (HPT) axis, whose effects on skeletal muscle thermogenesis are countered by the adipostatic signal(s) that continue to exert direct inhibitory effects on skeletal muscle to result in a net suppression of thermogenesis in this tissue. This enables sustained energy sparing for accelerating fat deposition, in part through compensatory hyperinsulinemia-induced de-novo lipogenesis in adipose tissues. Adapted from Dulloo and Jacquet [111]

Since skeletal muscle (which comprises 30–40% of body mass) is a quantitatively important contributor to daily EE and a major site for insulin-mediated glucose disposal, it follows that suppressed thermogenesis in this tissue would result in diminished muscle glucose utilization, thereby leading to compensatory hyperinsulinaemia. This in turn, would redirect the glucose spared from oxidation in skeletal muscle towards de-novo lipogenesis in adipose tissue (or in liver and then exported to adipose tissues), thereby contributing to catch-up fat, while concomitantly achieving blood glucose homeostasis (Fig. 2). Several features of this co-ordinated response have been validated in a rat model of catch-up fat driven by suppressed thermogenesis [105, 107, 114–119]. First, hyperinsulinemia is an early event (as early as day 1 of refeeding) and which is sustained during the entire phase of catch-up fat [116, 117]. Second, in-vivo assessed insulin sensitivity (and PI3 kinase signaling) is diminished in skeletal muscle [115, 118], concomitant to insulin hyperresponsiveness in adipose tissues associated with marked de-novo lipogenesis and increased adipocyte differentiation/proliferation [115–117]. Third, the secretory response of pancreatic beta-cells to glucose is enhanced [119], thereby implicating a role for pancreatic beta-cell hyperresponsiveness to glucose in the thrifty mechanisms that drive catch-up fat through glucose redistribution between skeletal muscle and adipose tissue.

To date, however, the sensor and signal components of this ‘adipose-specific’ control system that control thermogenesis in skeletal muscle remain unraveled. As for the effector component in skeletal muscle, the possibility arises that since refeeding is accompanied by a restoration of the neuroendocrine network (comprising insulin, leptin, SNS and HPT axis) that control thermogenesis in peripheral organs/tissues, the sustained suppression of skeletal muscle thermogenesis driving catch-up fat could result from a direct inhibitory effect of putative adipostatic signal(s) [120, 121] on intracellular modulators of thermogenesis in this tissue. Such signal-effector interactions would counter, and hence confer resistance to, the actions of the restored systemic neurohormonal network on muscle thermogenesis during weight regain.

Skeletal muscle hypothyroidism

Over the past decade, evidence has emerged to suggest that such skeletal muscle resistance to neurohormonal control of thermogenesis may be conferred by local alterations in metabolism of thyroid hormones through coordinated changes in deiodination enzymes that lead to diminished intracellular availability of T3, the main active thyroid hormone [112, 122–124]. These findings are in line with the relatively recent paradigm which considers that the deiodinases, besides playing a role in the homeostasis of circulating T3, also provide dynamic control of thyroid hormone signaling in peripheral tissues [125, 126], as depicted in Fig. 3.

Fig. 3.

The concentrations of circulating thyroid hormones, thyroxine (T4) and 3,5,3′-triiodothyronine (T3), which are iodinated compounds, are influenced by their local metabolism in peripheral tissues (including skeletal muscle) by the regulated expression of the deiodinase family of enzymes. Type 1 and type 2 deiodinases (D1 and D2) activate the conversion of T4 to the biologically more active hormone T3, whereas type 3 deiodinase (D3) is the main inactivator of both T4 and T3. Thus, there are two ways by which D3 reduces intracellular T3 availability (and hence T3 signaling): it prevents the conversion of T4 to T3 by catalyzing the conversion of T4 to reverse T3 (rT3), and it also catalyzes the degradation of T3 to T2

As indicated by the data in the rat model of thrifty catch-up fat (summarized in Table 2), despite the rapid restoration (in some cases overshoot) of components of the neuroendocrine network controlling thermogenesis (including circulating levels of the thyroid hormones), alterations in the local metabolism of thyroid hormones in the skeletal muscle that are observed during semistarvation, persist during catch-up fat [122–124]. There is a slower net formation of muscle T3 from its thyroxine (T4) precursor, i.e. diminished net muscle T3 neogenesis. This could be explained by the findings of a diminished expression of type 2 deiodinase (D2) which catalyzes the conversion of T4 to T3, and concomitant increase in the expression and activity of type 3 deiodinase (D3), the main thyroid hormone inactivating enzyme which degrades T4 to reverse T3 (rT3), as well as T3 to T2, thereby leading to diminished intracellular T3 availability. These alterations in local thyroid hormone metabolism - in particular diminished net T3 neogenesis and increased D3 protein/activity - could be demonstrated in skeletal muscle of different fiber composition [122–124].

Table 2.

Summary of main findings about hormonal changes and alterations in skeletal muscle metabolism in a rat model of semistarvation-refeeding in which catch-up fat during refeeding is driven by suppressed thermogenesis

	Semistarvation Weight loss	Refeeding Weight regain
Systemic ( Circulating )	vs. control	vs. control
Insulin	↓	↑
Leptin	↓	↑
Thyroid hormones
• Thyroxine (T4)	↓	=
• 3,5,3′-triiodothyronine (T3)	↓	=
Peripheral ( Skeletal muscle )
Thyroid hormone metabolism
• Net T3 neogenesis	↓	↓
• Deiodinase type 2 (D2)	↓	↓
• Deiodinase type 3 (D3)	↑	↑
Contractile properties
• Contraction-Relaxation Rate	↓	↓
• Slow/ Fast fibers Ratio	↑	↑
Protein turnover rate	?	↓

Symbols: ↑, higher; ↓, lower; =, no significant difference;?, not measured. Comparisons were made between semistarved rats and their controls at the end of 2 weeks of semistarvation and between refed rats and their controls after 1 week of controlled refeeding, with both refed and control rats consuming the same amount of food, but refed rats showing increased efficiency of body fat recovery [114, 115, 122–124]. Adapted from Dulloo [112]

Furthermore, several features of skeletal muscle metabolic and contractile properties which are well known to be associated with clinical hypothyroidism, and that lead to energy sparing [127–129], could also be demonstrated during weight regain (Table 2). First, there is a delay in hindlimb muscle contraction-relaxation kinetics [122]; a lower speed of the contraction–relaxation cycle being associated with reductions in ATP turnover [130–132]. Second, there is an increased proportion of slow (red, type I) muscle fibers at the expense of fast (white, type II) muscle fibers [122]; in terms of fuel economy, slow-twitch muscles are more efficient during contraction (use less ATP per unit force generated) than fast-twitch muscles [133, 134]. Third, there is a reduction in the rate of muscle protein turnover [123], an ATP-requiring substrate cycle whereby the synthesis of protein is opposed by its concomitant degradation [85].

Additional alterations in skeletal muscle metabolism observed during catch-up fat might also be attributed to diminished T3 signaling, namely: (i) diminished phosphatidylinositol-3-kinase (PI3K) activity and AMP-activated protein kinase (AMPK) activity [118], which have been shown to be required for hormonal control of skeletal muscle thermogenesis [87, 135, 136] and (ii) diminished skeletal muscle subsarcolemmal mitochondrial subpopulation [137], which has been implicated in cellular signaling [138, 139] as they are specialized to provide energy for metabolic processes associated with the plasma membrane. Furthermore, the above-mentioned diminished insulin-stimulated glucose utilization in skeletal muscle during catch-up fat [115, 117] is in accord with past demonstrations of a role for thyroid hormones in enhancing both basal and insulin-stimulated glucose transport in skeletal muscle [140, 141], and that hypothyroidism results in diminished insulin-stimulated glucose utilization [142, 143].

Collectively, these alterations in skeletal muscle contractile and metabolic properties, which are likely induced by D3-mediated reduction in T3 availability, can through their impact on diminished ATP utilization, diminished ATP turnover and increased mechanical efficiency, constitute energy-conservation mechanisms which contribute to the thrifty catch-up fat phenotype.

Thrifty catch-up fat: a risk for sarcopenic obesity

From an evolutionary perspective, the body’s fat stores play a crucial role in meeting an individual’s energy demands during extended periods of food scarcity, while simultaneously protecting the functional integrity of lean tissues and vital organs. Indeed, it is well established that the extent to which the body’s protein is utilized as fuel during starvation is inversely related to the initial (pre-starvation) level of fatness [144–146]. Consequently, a thrifty catch-up fat phenotype is evolutionary advantageous since it ensures a more rapid restoration of survival capacity conferred by prioritization in recovering the body’s fat stores (rather than lean tissues) in preparation for the next period of diminished food availability. It provides an alternative to hyperphagia for accelerating the replenishment of the fat stores and hence in enhancing survival capacity when food re-availability is limited. This thrifty catch-up fat, however, comes with tradeoffs as the underlying machinery for such thriftiness– postulated here to involve D3-induced skeletal muscle hypothyroidism– can compromise muscle functions and predispose to excess adiposity according to scenarios depicted in the conceptual framework shown in Fig. 4, and discussed below.

Fig. 4.

Conceptual mechanistic framework depicting how the state of skeletal muscle hypothyroidism that underlie the thrifty catch-up fat phenotype may impair muscle functionality and promote excess adiposity, which through large fluctuations in body weight and repeated weight cycling can lead to sarcopenic obesity. Note that fat overshooting (while an exacerbating factor) is not a requirement in proneness to sarcopenic obesity. Abbreviations: T3 = 3,5,3′-triiodothyronine; D3 = Type 3 deiodinase; FFM = Fat-free mass

Diminished muscle strength

First, the diminished muscle contractile properties which spare energy for catch-up fat may lead to diminish muscle strength, and can hence impact upon physical performance and physical activity, amid evidence in humans that full recovery from weight loss may take months or years and that muscle strength and physical performance may not be fully dependent on recovery of muscle mass [14, 147–150]. In fact, a slowed contraction-relaxation cycle, associated with a shift from fast-to-slow fiber composition, has long been implicated in the mechanisms by which malnutrition or clinical hypothyroidism leads to impaired skeletal muscle mechanical functions and physical disability [127–129, 147–150]. Furthermore, diminished thyroid hormone signaling in skeletal muscle can affect muscle function even in the absence of systemic hypothyroidism, as indicated by studies in euthyroid humans reporting that the ratio of T3/T4 in the circulation (an index of altered peripheral thyroid hormone metabolism) is positively associated with skeletal muscle strength or physical performance [151–154].

Insulin resistance

Second, given evidence of a role for thyroid hormones in enhancing insulin-stimulated glucose transport in skeletal muscle [140–143], a state of local hypothyroidism in this tissue could therefore be a contributing factor to the diminished muscle insulin sensitivity demonstrated during catch-up fat [115, 117]. Under conditions of catch-up fat during refeeding on a well-balanced (low fat) diet, blood glucose homeostasis is achieved by a concomitant increase in insulin-stimulated glucose utilization and de-novo lipogenesis in adipose tissue [115, 117]. However, this state of adipose tissue insulin hyperresponsiveness has been shown to be inhibited during isocaloric refeeding on diets high in saturated fat, and to result in glucose intolerance [117]. Thus, by blunting the enhanced capacity for glucose flux into adipose tissue during catch-up fat, a modern diet high in fat can offset the ability of adipose tissue to buffer against glucose spared from utilization as a result of muscle insulin resistance induced by local hypothyroidism. It is of interest to note that, independently of refeeding on diets low or high in dietary fat, skeletal muscle insulin resistance during catch-up is not accompanied by an increase in intramyocellular lipids [115, 118], thereby underscoring the thrifty catch-up fat phenotype as a state of skeletal muscle insulin resistance that may be dissociated from muscle lipotoxicity. The relevance of skeletal muscle insulin resistance per se, rather than muscle lipotoxicity in the pathogenesis of sarcopenic obesity, has been underscored by Poggiogalle et al. [155] who found that in middle-aged women with obesity, it was insulin resistance, and not muscle mass nor myosteatosis per se, that was associated with muscle weakness, resulting in the phenotype of dynapenic obesity.

Impaired myogenesis and muscle regeneration

Third, in addition to its role in skeletal muscle substrate metabolism and contractile functions, the local regulation of T3 is also crucial for muscle growth and regeneration through its regulation of the expression of muscle-specific genes involved in the various phases of myogenesis and muscle repair mechanisms upon which muscle functionality depends [156–158]. Myogenesis is a highly orchestrated sequence of events which involve the activation and proliferation of the muscle stem (satellite) cell population, followed by the differentiation and fusion of myoblasts, and subsequent growth and maturation of newly formed myotubes or myofibres. An emerging concept is that at the onset of the myogenic process, D3-mediated low intracellular T3 in activated and proliferating satellite cells protects against excessive local levels of thyroid hormone, thereby enabling the expansion of the satellite cell pool. The subsequent upregulation of D2, and resulting increase in intracellular T3, participates in the progression of the differentiation of activated satellite cells into the proliferative myoblast, and propels the terminal differentiation of myocytes into myotubes/myofibers [156–158]. Thus, while D3-induced lowering of intracellular T3 is important to support the initial satellite cells proliferation, sustained D3-induced repression of intracellular T3 (which is required for terminal differentiation) may impair myogenesis and regeneration of skeletal muscle, with consequential delays (or limitations) in the recovery of muscle mass, strength and functions. The crucial contribution of D3 to the thyroid hormone actions and local metabolic homeostasis of tissues is underscored by the fact that the activity of D3 is robustly increased in several tissues (including skeletal muscle) during sepsis [159, 160], and that targeted inhibition of D3 in skeletal muscle of septic rats restores thyroid hormone responsiveness, and protects muscle mass against sepsis-induced muscle atrophy [161].

Collateral fattening

Lastly, an indirect consequence of skeletal muscle hypothyroidism driving catch-up fat is that, under conditions of recovering large losses in both fat mass and FFM, the resulting asymmetry in body composition recovery, with fat mass being recovered earlier than FFM, can impact upon the duration of post-caloric restriction compensatory hyperphagia. There is indeed increasing evidence from human studies of weight regain after starvation or therapeutic slimming [162–168] that, besides a deficit in fat mass, a deficit in FFM can also contribute to subsequent compensatory hyperphagia, thereby underscoring interactions between deficits in muscle mass and the appetite-regulating centers of the brain to orchestrate altered feeding behavior [169, 170]. Consequently, as observed in some human studies of uncomplicated starvation and caloric restriction, the hyperphagic drive is still present even after fat mass recovery has reached completion, and persists until full recovery of FFM, albeit with concomitant deposition of fat [162, 163]. Such ‘collateral fattening’ [171], whereby excess fat is deposited as a result of the body’s attempt to counter a deficit in FFM through overeating, results in more body fat being regained than is lost, leading to excess adiposity. Consequently, a history of repeated weight cycling could, via repeated collateral fattening and fat overshooting, propel people of normal body weight or overweight along trajectories to obesity [169, 172], as illustrated using mathematical modeling [173], and consistent with the reports of several prospective studies that weight cycling is associated with future weight gain [174–176] and risks for cardiometabolic diseases [172, 176, 177].

Trajectories from weight fluctuations to sarcopenic obesity

The conceptual framework shown in Fig. 4– depicting the mechanisms by which a thrifty catch-up fat phenotype mediated by skeletal muscle hypothyroidism may lead to impairments in muscle functionality and proneness to excessive adiposity – can provide a mechanistic explanation for the findings of several retrospective studies linking weight cycling to risks for sarcopenic obesity. Indeed, a history of weight cycling among young-to-middle-aged or older people with overweight/obesity has been associated with increased fat mass, loss of FFM and an increased risk for sarcopenic obesity [178–181]. In particular, those with a history of severe weight cycling (more > 5 cycles) showed 4–5 times increased risks of low appendicular lean mass or low handgrip strength, and 6 times greater risk for sarcopenia compared to a control (no weight cycling) group [178]. Furthermore, frequent weight cycling over several years after intentional weight loss were associated with worse physical performance battery score and slower walking speed in women, and with weaker handgrip strength in men [181]. These links between weight cycling and sarcopenic obesity are reinforced by several randomized controlled trials of lifestyle intervention for weight loss in young, middle-aged or older adults with overweight/obesity reporting that those who regained weight showed greater recovery of fat mass relative to FFM [32, 33, 182], thereby predisposing them to sarcopenic obesity through repeated weight cycling.

The potential impact of the mechanisms underlying the thrifty catch-up fat phenotype in the development of sarcopenic obesity is particularly relevant to people who showed early growth perturbations followed by catch-up growth - a well recognized risk factor for later obesity and cardiometabolic diseases [12, 13, 23]. There is now compelling evidence that the dynamic process of infant catch-up growth is characterized by hyperinsulinemia and preferential catch-up fat rather than catch-up of lean tissue [13, 18–23], and that low birth weight infants (most of whom experience post-natal catch-up growth) have reduced muscle mass and muscle strength which are maintained across the life course [183–186]. While these associations may be driven by prenatal factors (e.g. suboptimal myogenesis and shortened telomere length during fetal development), there is evidence that they may also be driven by post-natal factors during catch-up growth. In the Dutch ABCD birth cohort study, infant catch-up growth after low birth weight (but not low birth weight per se or post-natal accelerated growth per se) could be associated with lower physical fitness, higher energy intake and diminished satiety response later during childhood [187, 188]. The demonstration that these impairments persisted after adjusting for multiple confounders (including FFM and objectively measured physical activity and sedentary behaviours) underscore the process of catch-up growth, and its underlying catch-up fat phenotype, as a critical window for post-natal programming of impaired muscle functionality and altered feeding behaviour that together confer risks for later sarcopenic obesity. That catch-up growth (and catch-up fat) could constitute a window for developmental programming for sarcopenia is also consistent with evidence from laboratory rodent models indicating that low birth weight followed by catch-up growth, but not low birth weight per se, induced an accelerated aging phenotype in skeletal muscle including telomere shortening and increased DNA damage, associated with oxidative stress and inflammation [189, 190].

Taken together, these studies provide links between catch-up fat and an accelerated aging phenotype in skeletal muscle in the context of developmental programming for early onset sarcopenia and sarcopenic obesity, amid proposals that changes observed in skeletal muscle with aging are similar to alterations associated with a decrease in thyroid hormone signaling [191], and that skeletal muscle is programmable and can ‘remember’, through adaptive epigenetic mechanisms, early-life metabolic stimuli that could affect its function later in adult life [192].

Concluding remarks

A role for altered peripheral tissue thyroid hormone deiodination, in particular a role for D3 in local tissue modulation of thyroid hormones, during prolonged energy deficit has long been overlooked. This is despite earlier reports highlighting an upregulation of D3 activity in skeletal muscle and liver of rodents and birds subjected to prolonged starvation or caloric restriction [193–195], and a robust induction of D3 in adult human tissues (including in skeletal muscle) of critically ill or injured patients [196, 197]. This induction of D3 seems particularly prominent in disease states associated with poor tissue perfusion [159, 160], possibly reflecting the body’s attempt to conserve energy by reducing local T3 availability and T3 signaling.

To-date, however, our understanding of how deiodinases are co-ordinated to regulate skeletal muscle growth and metabolism is still in its infancy. Among many unanswered questions are those regarding their temporal expressions in various cells populations within the skeletal muscle (including progenitor cells, infiltrated macrophages), as well as their subcellular locations which may influence their roles in the fine control of thyroid hormone signaling. Furthermore, the factors that regulate the activity of the deiodinases are not yet fully defined, amid questions as to whether the putative adipostatic signal(s) that are implicated in the feedback loop between adipose tissue and skeletal muscle thermogenesis interfere directly with the expression/activity of D3 and other deiodinases or rather with the regulatory factors that activate them, such as cyclic adenosine monophosphate (cAMP) and hypoxia-inducible factor 1α (HIF-1a) which induce D2 and D3, respectively [126]. Elucidation of these mechanisms could lead to the identification of novel therapeutic targets for enhancing skeletal muscle thermogenesis and myogenesis, while bypassing the adverse systemic side-effects of an elevation in circulating thyroid hormones and hence prove valuable in the management of obesity and sarcopenic obesity.

Author contributions

Single author AD wrote the manuscript and prepared all Tables and figures.

Funding

No funding was received to assist with the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.