Recent data have identified leptin as an afferent signal in a negative-feedback loop regulating the mass of the adipose tissue. High leptin levels are observed in obese humans and rodents, suggesting that, in some cases, obesity is the result of leptin insensitivity. This hypothesis was tested by comparing the response to peripherally and centrally administered leptin among lean and three obese strains of mice: diet-induced obese AKR͞J, New Zealand Obese (NZO), and A y . Subcutaneous leptin infusion to lean mice resulted in a dose-dependent loss of body weight at physiologic plasma levels. Chronic infusions of leptin intracerebroventricularly (i.c.v.) at doses of 3 ng͞hr or greater resulted in complete depletion of visible adipose tissue, which was maintained throughout 30 days of continuous i.c.v. infusion. Direct measurement of energy balance indicated that leptin treatment did not increase total energy expenditure but prevented the decrease that follows reduced food intake. Diet-induced obese mice lost weight in response to peripheral leptin but were less sensitive than lean mice. NZO mice were unresponsive to peripheral leptin but were responsive to i.c.v. leptin. A y mice did not respond to subcutaneous leptin and were 1͞100 as sensitive to i.c.v. leptin. The decreased response to leptin in diet-induced obese, NZO, and A y mice suggests that obesity in these strains is the result of leptin resistance. In NZO mice, leptin resistance may be the result of decreased transport of leptin into the cerebrospinal f luid, whereas in A y mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus.

The effect of 7 wk consumption of a diet containing 32.6% of kilocalories as fat [condensed milk (CM) diet] on body composition and energy intake was evaluated in nine strains of inbred mice (AKR/J, C57L/J, A/J, C3H/HeJ, DBA/2J, C57BL/6J, SJL/J, I/STN, and SWR/J). Control animals were fed a high-carbohydrate diet containing 11.6% of energy as fat (Purina Rodent Chow diet). Relative to Chow diet controls, the CM diet significantly increased carcass lipid content in six strains (AKR/J, C57L/J, A/J, C3H/HeJ, DBA/2J, and C57BL/6J), but had no or a marginal effect on adiposity in three strains of mice (SJL/J, I/STN, and SWR/J). The obesity produced by the CM diet in six strains was not due to hyperphagia. Only one of six (AKR/J) of the strains that increased adiposity on the CM diet consumed more energy than controls during the 7 wk of the experiment. The identification of inbred mouse strains that are sensitive to dietary obesity, vs. others that are resistant, provides a useful tool to pursue the metabolic and genetic basis of this trait in the mouse.

To determine the function of VGF, a secreted polypeptide that is synthesized by neurons, is abundant in the hypothalamus, and is regulated in the brain by electrical activity, injury, and the circadian clock, we generated knockout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyperactive, and infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesis is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that the study of lean VGF mutant mice may provide insight into wasting disorders and, moreover, that pharmacological antagonism of VGF action(s) might constitute the basis for treatment of obesity.

]. Postures, limb movements, and jumping were tested using a timed protocol of specific activities. Walking and running were tested using a 60-meter track, on which subjects walked and ran at 6 self-selected speeds. Stair climbing and descending were tested by timing subjects who climbed and descended a flight of stairs at two different speeds. Results: Correct identification rates averaged 98.9% for posture and limb movement type and 98.5% for gait type. Pooled correlation between predicted and actual speeds of walking and running was high (r ϭ 0.986, p Յ 0.0001). Discussion: IDEEA accurately measured duration, frequency, type, and intensity of a variety of daily PAs.

The relationship between resting energy expenditure (REE) and metabolically active fat-free mass (FFM) is a cornerstone in the study of physiological aspects of body weight regulation and human energy requirements. Important questions, however, remain unanswered regarding the observed linear REE-FFM association in adult humans. This led us to develop a series of REE-body composition models that provide insights into the widely used simple linear REE-FFM prediction model derived experimentally in adult humans. The new models suggest that the REE-FFM relationship in mammals as a whole is curvilinear, that a segment of this function within a FFM range characteristic of adult humans can be fit with a linear equation almost identical to that observed from a composite review of earlier human studies, and that mammals as a whole exhibit a decrease in the proportion of FFM as high metabolic rate organs with greater FFM. The present study thus provides a new approach for examining REE-FFM relationships, advances in a quantitative manner previously observed albeit incompletely formulated REE-body composition associations, and identifies areas in need of additional research.

Several prospective epidemiologic studies over the past 4 y concluded that ingestion of caffeinated and decaffeinated coffee can reduce the risk of diabetes. This finding is at odds with the results of trials in humans showing that glucose tolerance is reduced shortly after ingestion of caffeine or caffeinated coffee and suggesting that coffee consumption could increase the risk of diabetes. This review discusses epidemiologic and laboratory studies of the effects of coffee and its constituents, with a focus on diabetes risk. Weight loss may be an explanatory factor, because one prospective epidemiologic study found that consumption of coffee was followed by lower diabetes risk but only in participants who had lost weight. A second such study found that both caffeine and coffee intakes were modestly and inversely associated with weight gain. It is possible that caffeine and other constituents of coffee, such as chlorogenic acid and quinides, are involved in causing weight loss. Caffeine and caffeinated coffee have been shown to acutely increase blood pressure and thereby to pose a health threat to persons with cardiovascular disease risk. One short-term study found that ground decaffeinated coffee did not increase blood pressure. Decaffeinated coffee, therefore, may be the type of coffee that can safely help persons decrease diabetes risk. However, the ability of decaffeinated coffee to achieve these effects is based on a limited number of studies, and the underlying biological mechanisms have yet to be elucidated.

The purpose of this study was to validate the Intelligent Device for Energy Expenditure and Activity (IDEEA) for estimation of energy expenditure during a variety of activities. An additional aim was to improve the accuracy of the estimation of energy expenditure of physical activity based on second-by-second information of type, onset, and duration of activity. Methods: This study included two tests: a mask calorimetry test with 27 subjects [age ϭ 33.7 Ϯ 13.8 (mean Ϯ SD) yr; BMI ϭ 24.8 Ϯ 4.8 kg•m Ϫ2 ] and a respiratory chamber calorimetry test with 10 subjects (age ϭ 32.9 Ϯ 12.4 yr; BMI ϭ 26.1 Ϯ 5.6 kg•m Ϫ2). In the mask test, the subjects performed activities (sitting, standing, lying down, level treadmill walking, and running at different speeds) for 50-min durations. For the chamber test, subjects lived in the metabolic chamber for 23 h and performed three exercise sessions to compensate for the confined environment. Results: The results showed significant correlations (P Ͻ 0.0001) between energy expenditure estimated by IDEEA and energy expenditure measured by the calorimeters with an accuracy Ͼ 95%. After corrections for the decrease in sleeping metabolic rate, the estimation accuracy for the chamber test was increased by 1-96.2%, whereas the estimation accuracy for nighttime activity was significantly improved by 4-99%. Conclusion: IDEEA provides a suitable method for estimating the energy expenditure of physical activity. It provides both instantaneous and cumulative estimates of energy expenditure over a given period.

Targeted deletion of the gene encoding the neuronal and neuroendocrine secreted polypeptide VGF (nonacronymic) produces a lean, hypermetabolic mouse. Consistent with this phenotype, VGF mRNA levels are regulated in the hypothalamic arcuate nucleus in response to fasting. To gain insight into the site(s) and mechanism(s) of action of VGF, we further characterized VGF expression in the hypothalamus. Double-label studies indicated that VGF and pro-opiomelanocortin were coexpressed in lateral arcuate neurons in the fed state, and that VGF expression was induced after fasting in medial arcuate neurons that synthesize neuropeptide Y (NPY). Like NPY, VGF mRNA induction in this region of the hypothalamus in fasted mice was inhibited by exogenous leptin. In leptin-deficient ob/ob and receptor-mutant db/db mice, VGF mRNA levels in the medial arcuate were elevated. To identify neural pathways that are functionally compromised by Vgf ablation, VGF mutant mice were crossed with obese A(y)/a (agouti) and ob/ob mice. VGF deficiency completely blocked the development of obesity in A(y)/a mice, whereas deletion of Vgf in ob/ob mice attenuated weight gain but had no impact on adiposity. Hypothalamic levels of NPY and agouti-related polypeptide mRNAs in both double-mutant lines were dramatically elevated 10- to 15-fold above those of wild-type mice. VGF-deficient mice were also found to resist diet- and gold thioglucose-induced obesity. These data and the susceptibility of VGF mutant mice to monosodium glutamate-induced obesity are consistent with a role for VGF in outflow pathways, downstream of hypothalamic and/or brainstem melanocortin 4 receptors, that project via the autonomic nervous system to peripheral metabolic tissues and regulate energy homeostasis.