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.

Keywords: Catch-up growth; Deiodinases; Metabolic adaptation; Obesity; Thyroid hormones; Weight cycling.

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]

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]

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

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