The contribution of reduced thermogenesis and fat oxidation to obesity and its metabolic complications

In rodents, there is compelling evidence that obesity may develop as a result of a deficit in energy expenditure and more specifically in adaptive thermogenesis. A feature of most animal models of obesity, whether genetic-or lesion-induced, is a decreased energy expenditure and an abnormally low BAT thermogenic response to cold or feeding;26 in these models, even when food intake is restricted to that of wild-type or control animals (a maneuver termed pair feeding) marked obesity still develops.

The contribution of reduced energy expenditure to human obesity is less clear. The concept was supported by early epidemiological studies showing that obese subjects maintained their obese state with self-reported energy intakes that were on average less than those of lean subjects, but has been challenged by more recent studies - using the doubly labeled water method, which allows capturing of total energy expenditure for long periods of time with the individual under free-living conditions - indicating that obese subjects have a greater average energy expenditure than do lean and normal-weight subjects (reviewed in reference 27). The increase of total energy expenditure with increasing weight or body mass index is dramatic, and is probably a consequence of a parallel increase of fat-free mass, which is the single best determinant of resting energy expenditure.28

Nevertheless, there is evidence that a reduced rate of energy expenditure is a risk factor for both body weight gain and resistance to weight loss in humans. In a now classic study conducted in Pima Indians, it was found that low 24 h energy expenditure, normalized for lean body mass, predicted future weight gain during follow-up.29 In another study, activation of non-exercise activity thermogenesis proved to be the principal mediator of resistance to fat gain during overfeeding, so that individuals that failed to activate this component of energy expenditure were those that gained more weight.30 There are also studies suggesting that specifically a deficit in the thermic response to food, as a consequence of a reduced sympathetic response to feeding, may contribute to human obesity, although this is a highly controversial issue (reviewed in references 31 and 32).

A low capacity to oxidize fat may also contribute to obesity, particularly when dietary fat is in large supply. In fact, human epidemiological studies point to a reduced rate of fat oxidation as a risk marker for body weight gain, independent of low energy expenditure.33'34 Moreover, formerly obese individuals of normal weight have been shown to have a lower rate of fat oxidation compared with control, never-obese subjects.3536

Besides and beyond contributing to increased fat mass (obesity), decreased fat oxidation and thermogenesis may result in an excess of available fatty acids to muscle, liver, pancreatic p cells and other non-adipose cells. Lipid accumulation can lead to functional impairments in these cells (lipotoxicity), and has been related to the development of insulin resistance, type 2 diabetes and other pathologies linked to obesity and the metabolic syndrome (reviewed in references 37 and 38). Because the activity of the UCPs may facilitate fat oxidation in the organism (see Section 4.2.1), it may help avoiding lipid accumulation in non-adipose cells and derived lipotoxic-ity. For instance, intramyocellular fat accumulation is highly correlated with insulin resistance and may be prevented through the activity of muscle UCP3, which is normally up-regulated under conditions of high fatty acid supply to muscles.39 Also in this context, it has been suggested that brown fat function may be important for the modulation of systemic insulin sensitivity, because a reduced expression of genes involved in brown adipogene-sis was found in subcutaneous WAT of non-obese, insulin-resistant human subjects compared with non-obese, insulin-sensitive subjects.40,41

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