Activity limitations related to cold hypersensitivity in patients with hand injuries.

BACKGROUND: Knowledge of specific activity limitations due to cold hypersensitivity is sparse. PURPOSE: To explore activity limitations caused by cold hypersensitivity and the associated environmental factors in patients with hand injuries. STUDY DESIGN: Descriptive study. METHODS: Seventy-seven patients with multiple tissue hand injuries described activity limitations related to cold hypersensitivity in questionnaires six and/or 12 months after surgery. To characterize the activity limitations, we performed a quantitative content analysis applying the International classification of functioning and health (ICF). RESULTS: The respondents described on average 3.6 cold related activity limitations in leisure and/or work. The activities were most frequently (n) assigned to the ICF domains d920 Recreation and leisure (95), d440 Fine hand use (77), and d850 Remunerative employment (39). The most common related environmental factors were Products and technology for e140 Culture, recreation and sport (79) and for e135 Employment (71), respectively, and e225 Climate (71). Gloves were both a facilitator and a barrier for activity performance. CONCLUSION: The impact of cold hypersensitivity on activity was related to both the activity and the environment. The results call for clinical interventions and product development, for example of gloves, to help patients solve their cold related activity limitations.

Microcirculatory response to cold stress test in the healthy hand.

OBJECTIVE: Cold sensitivity of the fingers is common in several conditions. It has been linked to digital vasospasm, microvascular dysfunction, and neural mechanisms. This study aimed to investigate the normal digital microvascular response to a cold stress test in healthy individuals using Laser Speckle Contrast Imaging (LSCI). METHODS: Twenty-six healthy individuals, mean age 31 (SD 9) years were included. Skin perfusion of digits II-V was measured using Laser Speckle Contrast Imaging before and after a standardized cold stress test. Changes in skin perfusion from baseline were analyzed between hands, digits, and sexes. RESULTS: Skin perfusion was significantly (p < 0.0001) affected by cold provocation in both the cold exposed and the contralateral hands in all participants of the study. This effect was significantly different between the radial (digit II and III) and the ulnar (digit V) side of the hands (p < 0.001). There was a trend towards a larger decrease in perfusion in men (ns), and a faster recovery to baseline values in women (ns). A larger inter subject variability was seen in perfusion values in women. CONCLUSIONS: The normal microvascular response to cold provocation may involve both centrally and regionally mediated processes. When exposing one hand to a cold stress test, the contralateral hand responds with simultaneous but smaller decreases in perfusion.

LETMD1 is required for mitochondrial structure and thermogenic function of brown adipocytes.

Obesity and metabolic disorders caused by energy surplus pose an increasing concern within the global population. Brown adipose tissue (BAT) dissipates energy through mitochondrial non-shivering thermogenesis, thus representing a powerful agent against obesity. Here we explore the novel role of a mitochondrial outer membrane protein, LETM1-domain containing 1 (LETMD1), in BAT. We generated a knockout (Letmd1KO ) mouse model and analyzed BAT morphology, function and gene expression under various physiological conditions. While the Letmd1KO mice are born normally and have normal morphology and body weight, they lose multilocular brown adipocytes completely and have diminished mitochondrial abundance, DNA copy number, cristae structure, and thermogenic gene expression in the intrascapular BAT, associated with elevated reactive oxidative stress. In consequence, the Letmd1KO mice fail to maintain body temperature in response to acute cold exposure without food and become hypothermic within 4 h. Although the cold-exposed Letmd1KO mice can maintain body temperature in the presence of food, they cannot upregulate expression of uncoupling protein 1 (UCP1) and convert white to beige adipocytes, nor can they respond to adrenergic stimulation. These results demonstrate that LETMD1 is essential for mitochondrial structure and function, and thermogenesis of brown adipocytes.

Evaluation of Cold Sensitivity in Patients With Upper Extremity Nerve Compression Syndromes: A Scoping Review.

PURPOSE: The aim of this study was to review the literature to determine the prevalence of cold sensitivity in upper extremity nerve compression syndromes and the impact of treating nerve compression syndromes on cold sensitivity. METHODS: Following a standardized scoping review protocol, this study included interventional and observational study designs assessing patients with cold sensitivity and upper extremity nerve compression syndromes. Review articles, case reports, and small case series (n < 5) were excluded. The abstracts and eligible full texts were screened by 2 independent reviewers. Data were extracted and reported according to PRISMA extension for scoping reviews statement. RESULTS: Three databases were searched (Ovid MEDLINE, Ovid EMBASE, and CINAHL on EBSCO); 274 references were reviewed. Fifteen studies from the database search and 8 studies from the reference search were eligible for this review (n = 23). Two interventional and 21 observational studies were identified. The most common method for assessing cold sensitivity was cold pain threshold testing (n = 12), followed by subjective patient reporting (n = 4). The Cold Intolerance Symptom Severity questionnaire was the most common validated patient-reported outcome questionnaire used in the studies (n = 3). Cold sensitivity was most commonly reported in carpal tunnel syndrome (96% of the studies). The prevalence of cold sensitivity in nerve compression syndromes ranged from 20% to 69%. Nerve decompression improved the severity of cold sensitivity in 5 of 6 studies where cold sensitivity was studied. CONCLUSIONS: There is heterogenicity in the studies assessing cold sensitivity in nerve compression syndromes. Despite moderate prevalence in patients with carpal tunnel syndrome, cold sensitivity is understudied. Within the limitations of eligible studies reviewed, surgical decompression improved the severity of cold sensitivity in some studies. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Cold intolerance and neuropathic pain after peripheral nerve injury in upper extremity.

Cold intolerance and pain can be a substantial problem in patients with peripheral nerve injury. We aimed at investigating the relationships among sensory recovery, cold intolerance, and neuropathic pain in patients affected by upper limb peripheral nerve injury (Sunderland type V) treated with microsurgical repair, followed by early sensory re-education. In a cross-sectional clinical study, 100 patients (male/female 81/19; age 40.5 ± 14.8 years and follow-up 17 ± 5 months, mean ± SD), with microsurgical nerve repair and reconstruction in the upper extremity and subsequent early sensory re-education, were evaluated, using Cold Intolerance Symptoms Severity questionnaire-Italian version (CISS-it, cut-off pathology >30/100 points), CISS questionnaire-12 item version (CISS-12, 0-46 points-grouping: healthy that means no cold intolerance [0-14], mild [15-24], moderate [25-34], severe [35-42], very severe [43-46] cold intolerance), probability of neuropathic pain (DouleurNeuropathique-4; [DN4] 4/10), deep and superficial sensibility, tactile threshold (monofilaments), and two-point discrimination (cutoff S2; Medical Research Council scale for sensory function; [MRC-scale]). A high CISS score is associated with possible neuropathic pain (DN4 ≥ 4). Both a low CISS-it score (ie, < 30) and DN4 < 4 is associated with good sensory recovery (MRC ≥ 2). In conclusion patients affected by upper limb peripheral nerve injuries with higher CISS scores more often suffer from cold intolerance and neuropathic pain, and the better their sensory recovery is, the less likely they are to suffer from cold intolerance and neuropathic pain.

Effect of Forearm Warming Compared to Hand Warming for Cold Intolerance Following Upper Extremity Trauma.

PURPOSE: This study evaluated the effect of forearm or hand warming versus bare hand conditions to improve cold-induced symptoms and skin temperatures in hand trauma patients. METHODS: Adults with symptoms of cold intolerance at least 3 months following hand trauma and age-/sex-matched controls were included. Testing sessions (bare hand, hand warming, forearm warming) were completed in a climate laboratory with continuous temperature monitoring. Outcomes included physical findings (skin temperature) and self-report symptoms (thermal comfort, pain). RESULTS: Eighteen participants (9 hand trauma patients, 9 control subjects) underwent testing. More severe cold intolerance was associated with higher Disabilities of the Arm, Shoulder, and Hand scores. With bare hands, skin temperatures changed significantly from baseline to cold exposure and to rewarming. Hand trauma patients had the lowest skin temperatures with cold exposure in the injured digits (14.3°C ± 3.5°C) compared with the contralateral uninjured (16.9°C ± 4.1°C) digits. Compared with bare hands, wearing gloves significantly increased the minimum temperature during cold exposure and the maximum temperature after rewarming. Patients reported higher pain with cold exposure. All participants reported significantly more comfort with less coldness with forearm and hand warming. CONCLUSIONS: There was cold response variability in hand trauma patients and control subjects. Hand trauma patients had greater changes in skin temperature during cold exposure that improved with glove warming. Continuous temperature monitoring identified subtle physiological changes associated with cold-induced pain and with warming interventions. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Validity and reliability of the Turkish version of the Cold Intolerance Symptom Severity Questionnaire

Background/aim: The aim of this study was to determine validity and reliability of the Turkish version of the Cold Intolerance Symptom Severity (CISS-T) Questionnaire. Materials and methods: The translation and back translation steps of the study were based on the Beaton guidelines. Sixty-eight patients between 18 and 65 years old with cold intolerance after amputation, replantation, multiple crush syndrome, and peripheral nerve injury were included in the study. Patients completed the Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH), the SF-36 Quality of Life Questionnaire, and the single questions assessing the cold sensitivity and cold intolerance once and the final version of the CISS-T twice with a 7-day interval. Results: The internal consistency (Cronbach α = 0.844) and test-retest reliability (r = 0.938) of CISS-T were assessed and both were considerably high. Also, the correlations between the scores of the CISS-T, DASH-T, SF-36-T, and the single questions were analyzed by Spearman's correlation coefficient. The CISS-T showed an excellent correlation with the single questions (rho = 0.8 and 0.877), a good and negative correlation with the pain subscale of the SF-36 (rho = 0.617), and a moderate correlation with the DASH-T (rho = 0.592). Conclusion: As a result, the CISS-T is a valid and reliable instrument to assess the severity of cold intolerance.

Non-linear shift from grassland to shrubland in temperate barrier islands.

Woody plant encroachment into grasslands is a major land cover change taking place in many regions of the world, including arctic, alpine and desert ecosystems. This change in plant dominance is also affecting coastal ecosystems, including barrier islands, which are known for being vulnerable to the effects of climate change. In the last century, the woody plant species Morella cerifera L. (Myricaceae), has encroached into grass covered swales in many of the barrier islands of Virginia along the Atlantic seaboard. The abrupt shift to shrub cover in these islands could result from positive feedbacks with the physical environment, though the underlying mechanisms remain poorly understood. We use a combination of experimental and modeling approaches to investigate the role of climate warming and the ability of M. cerifera to mitigate its microclimate thereby leading to the emergence of alternative stable states in barrier island vegetation. Nighttime air temperatures were significantly higher in myrtle shrublands than grasslands, particularly in the winter season. The difference in the mean of the 5% and 10% lowest minimum temperatures between shrubland and grassland calculated from two independent datasets ranged from 1.3 to 2.4°C. The model results clearly show that a small increase in near-surface temperature can induce a non-linear shift in ecosystem state from a stable state with no shrubs to an alternative stable state dominated by M. cerifera. This modeling framework improves our understanding and prediction of barrier island vegetation stability and resilience under climate change, and highlights the existence of important nonlinearities and hystereses that limit the reversibility of this ongoing shift in vegetation dominance.

Prevalence of Endometriosis and Its Symptoms among Young Jordanian Women with Chronic Pelvic Pain Refractory to Conventional Therapy.

OBJECTIVE: This study sought to explore the prevalence and clinical manifestations of endometriosis in young women with chronic pelvic pain (CPP) refractory to conventional medical therapy. METHODS: This prospective clinical interventional study was conducted in two general and private hospitals in the city of Al-Karak in Jordan. A total of 28 female patients aged ≤21 who had CPP refractory to conventional medical therapy were recruited during the years 2010-2014. The intervention used in the study was laparoscopy. Endometriosis was staged according to the American Society for Reproductive Medicine classification. The main outcome measures were the presence and stage of endometriosis at laparoscopy, the presence of cold intolerance, and the severity and duration of pain symptoms. RESULTS: The mean age of participants was 18.4 (range 15 to 21). Endometriosis was found in 20 of 28 participants (71.4%), as follows: stage I, 9 of 20 (45.0%); stage II, 8 of 20 (40%); stage III, 2 of 21 (10%); and stage IV, 1 of 21 (5%). Notably, 16 of 28 (57.1%) of all participants reported cold intolerance, including 14 of 20 (70%) with endometriosis and 2 of 8 (25%) without endometriosis (Fisher exact [1-tail] P = 0.039). There was no association between stage of disease and age distribution (≤18 and >19 to 21; P = 0.7) or with duration of symptoms (≤2 and >2 years) and the presence of cold intolerance (P > 0.05). However, severity of pain symptoms (<7 vs. ≥7, as measured by the visual analogue scale [VAS]) was associated significantly with stage of disease (P = 0.011). CONCLUSION: The prevalence of endometriosis among young women with CPP refractory to conventional therapy was high, mainly in the mild stage. Cold intolerance was highly associated with endometriosis.

Cold intolerance after nerve injury.

Cold intolerance after nerve injury can be severe and has been associated with high levels of pain and disability. This article provides an overview of the assessment and nonoperative management of cold-induced symptoms after peripheral nerve injury. A comprehensive evaluation should include both objective measures such as skin temperatures and subjective tools to assess the patient's perspective and impact of the symptoms. Management of the patient with cold intolerance remains challenging and should include adaptive strategies, warming interventions, and desensitization conditioning programs to minimize cold-induced pain and hyperresponses.

Evaluation of a home treatment program for cold hypersensitivity using a classical conditioning procedure in patients with hand and arm injuries.

STUDY DESIGN: Case series. INTRODUCTION: A home treatment program using a classical conditioning procedure to decrease cold hypersensitivity has potential to reduce symptoms. PURPOSE: To evaluate a home treatment program for cold hypersensitivity using a classical conditioning procedure in patients who are cold hypersensitive after hand and arm injuries. METHODS: A series of 22 patients followed a classical conditioning procedure consisting of exposing the body to cold outdoor temperatures and immersing the hands in warm water, every other day, for five weeks. The McCabe Cold Sensitivity Severity scale (CSS) was used to measure cold hypersensitivity twice before treatment, at four weeks, and at one year after treatment; Likert scales was used for the patients ratings of improvements. A cold stress test was performed to evaluate rewarming capacity in injured fingers. RESULTS: From the 20 patients, who returned questionnaires at all assessment points, 9 reported a small and three reported a moderate improvement in cold hypersensitivity after treatment. There was a trend toward improvement in the CSS (median 36; interquartile range--19 to 60) and in the rewarming pattern of fingers that were initially slow to rewarm. The improvements were sustained or increased at one-year follow-up. CONCLUSION: These preliminary results suggest that the classical conditioning procedure to treat cold hypersensitivity has potential and should be further explored in a trial with more rigorous design.

Self-management strategies used by patients who are hypersensitive to cold following a hand injury. A prospective study with two years follow-up.

STUDY DESIGN: Prospective cohort study. INTRODUCTION: Knowledge of the strategies used by patients with injuries of the hand to manage cold hypersensitivity should guide information given by health-care workers. PURPOSE: To explore the use of cold-associated self-management strategies in patients with severe hand injuries. METHODS: Seventy patients being cold hypersensitive following a hand injury, reported use of strategies to limit cold-induced symptoms in the injured hand(s) and the severity of cold-associated activity limitations one and two years after surgery. RESULTS: The patients used several strategies, including clothing (100%), use of own body (movement/use of muscles to produce heat or massage of the fingers) (94%), and heating aids (48%), but were still limited in valued cold-associated activities two years after surgery. The number of patients staying indoors, using heating aids and hand wear indoors and during summer-time increased with severity of cold hypersensitivity. Patients both implemented and discontinued different strategies after the first year, but for most strategies, the proportions of users were quite stable. CONCLUSION: The most common strategies used to limit cold-induced symptoms in the injured hand(s) were clothing and use of own body. Many patients also seemed to benefit from using heating aids. After one year, a number of patients still experimented in finding the best strategies and were still limited in valued cold-associated activities. LEVEL OF EVIDENCE: 2b.

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance.

The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step of mitochondrial ß-oxidation. Patients with VLCAD deficiency present with hypoketotic hypoglycemia and cardiomyopathy, which can be exacerbated by fasting and/or cold stress. Global VLCAD knockout mice recapitulate these phenotypes: mice develop cardiomyopathy, and cold exposure leads to rapid hypothermia and death. However, the contribution of different tissues to development of these phenotypes has not been studied. We generated cardiac-specific VLCAD-deficient (cVLCAD(-/-)) mice by Cre-mediated ablation of the VLCAD in cardiomyocytes. By 6 mo of age, cVLCAD(-/-) mice demonstrated increased end-diastolic and end-systolic left ventricular dimensions and decreased fractional shortening. Surprisingly, selective VLCAD gene ablation in cardiomyocytes was sufficient to evoke severe cold intolerance in mice who rapidly developed severe hypothermia, bradycardia, and markedly depressed cardiac function in response to fasting and cold exposure (+5°C). We conclude that cardiac-specific VLCAD deficiency is sufficient to induce cold intolerance and cardiomyopathy and is associated with reduced ATP production. These results provide strong evidence that fatty acid oxidation in myocardium is essential for maintaining normal cardiac function under these stress conditions.

Carpal tunnel release in patients with diabetes: a 5-year follow-up with matched controls.

PURPOSE: To compare clinical outcomes 5 years after carpal tunnel release among patients with and without diabetes. METHODS: In a prospective consecutive series, 35 patients with diabetes (median age, 54 y; 15 type 1 and 20 type 2 diabetes) with carpal tunnel syndrome were age- and sex-matched with 31 control patients without diabetes (median age, 51 y) with idiopathic carpal tunnel syndrome. Exclusion criteria were other nerve entrapment, cervical radiculopathy, inflammatory joint disease, thyroid disorder, previous wrist fracture, and long-term exposure to vibrating tools. Participants were examined independently at baseline, 1 year, and 5 years after surgery for sensory function (Semmes-Weinstein), motor function (abductor pollicis brevis muscle strength and grip strength), cold intolerance, and completion of the Boston Carpal Tunnel Questionnaire symptom severity and functional status score. RESULTS: Five years after surgery, the overall attendance rate for clinical examinations and completion of the Boston Carpal Tunnel Questionnaire were 86% and 95%, respectively. Between 1 and 5 years after surgery, there was a tendency toward a decrease in sensory function but an increase in motor function, with no statistically significant difference between groups. Cold intolerance demonstrated long-term significant improvement for patients with diabetes. The improvement in symptom severity and functional status score, as well as the large effect size, were maintained at 5 years in both patient groups. CONCLUSIONS: Long-term improvement in patients with diabetes remained after carpal tunnel release to the same extent as for patients without diabetes. Furthermore, improvement in cold intolerance in patients with diabetes suggests the potential for the long-term regeneration of small nerve fibers. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic I.

Serum levels of biomarkers related to severity staging of Raynaud's phenomenon, neurosensory manifestations, and vibration exposure in patients with hand-arm vibration injury.

Our aim was to explore possible relationships between serum levels of biomarkers in patients with hand-arm vibration injury in relation to the severity of the vascular, i.e., Raynaud's phenomenon (RP), and neurosensory manifestations, the current exposure level, and the duration of exposure. This study was of case series design and involved 92 patients diagnosed with hand-arm vibration injury. Jonckheere's trend test was used to assess any association between serum levels of biomarkers and RP as well as neurosensory manifestations, graded by the International Consensus Criteria. Generalized linear models with adjustment for possible confounders were also used for associations between serum levels of biomarkers and; (1) severity of RP recorded as the extent of finger blanching calculated with Griffin score, (2) vibration perception thresholds, (3) magnitude of current exposure as [A(8); (m/s2)] value, and (4) the duration of exposure in years. Serum levels of thrombomodulin, von Willebrand factor, calcitonin gene related peptide (CGRP), heat shock protein 27, and caspase-3 were positively associated with severity of RP. Serum levels of CGRP were positively associated with the neurosensory component. No associations with exposure were shown for these biomarkers. For Intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, no associations were found with neither severity nor exposure. Levels of serum biomarkers associated with endothelial injury or dysfunction, inflammation, vasodilation, neuroprotection, and apoptosis were positively associated with the severity of hand-arm vibration injury.

Surprising Diagnosis of Myxedema Crisis In-Patient Who Presented With Altered Sensorium.

Hypothyroidism, a disorder of decreased thyroid hormone secretion diagnosed by increased thyroid stimulating hormone (TSH) and low free triiodothyronine (FT3) and free thyroxine (FT4) levels, is classified as primary and secondary hypothyroidism, depending on the pathology. Raised TSH levels are associated with primary hypothyroidism, while decreased levels of TSH are seen in secondary hypothyroidism. With the easy availability of diagnostic tests, hypothyroidism can be detected and managed early but can be life-threatening if not treated within time. Manifestations of hypothyroidism are dry skin, hoarseness of voice, weight gain, constipation, cold intolerance, fatigue, and lethargy; however, the clinical presentation can differ as per age and sex and person to person. Here, we present one such case, which was brought to the emergency room with a history of altered sensorium, hypotension, and swelling over the bilateral lower limbs and face, with a surprise diagnosis of myxedema crisis. The uniqueness of this case is the omnipresent availability of early diagnosis and treatment in this era. still got a female patient with altered sensorium who was diagnosed to be a myxedema crisis which was given a lesser thought in our provisional diagnosis.

Managing cold intolerance after hand injury: A systematic review.

OBJECTIVES: This systematic review seeks to understand whether cold intolerance (CI) improves with time and if there is any role for management strategies such as behavioural therapy, surgery, or pharmacotherapy. METHODS: Two independent reviewers used a predefined search strategy to query MEDLINE, PubMed, Embase, CINAHL, Cochrane Library, Web of Science and Google Scholar databases. Articles written in English, Studies of interventions (such as pharmacotherapy or behavioural therapy) for cold intolerance in adult patients with a history of hand injury along with prevalence over time were included for review. RESULTS: Seventeen studies were included, with twelve prognostic studies of the effect of time on CI, four studies of self management/behavioural therapies, and a single study of surgical treatment of neuromas. No studies of pharmacotherapies were identified for inclusion in the hand injury literature. Most studies (76.4%) were either prevalence or prospective cohort studies; no level I or II evidence studies were included. CONCLUSIONS: Cold intolerance does not resolve over time for the vast majority of patients. Behavioral and self-management studies have low efficacy and studies presented had a high risk of bias. There is a lack of evidence for the use of pharmacotherapy in CI and this could be considered for future studies.

Treatment of cold intolerance following finger pulp amputations: a case comparison between immediate finger replantation and delayed pulp and digital arterial arch reconstruction with flow-through free hypothenar flap.

We report a unique case of cold intolerance following identical fingertip amputations of two fingers on the same hand. The index finger was replanted and the middle finger was reconstructed with a free flow-through hypothenar perforator flap to anatomically restore the digital arterial arch circulation and successfully treat cold intolerance.

Obesity caused by an OVOL2 mutation reveals dual roles of OVOL2 in promoting thermogenesis and limiting white adipogenesis.

Using random germline mutagenesis in mice, we identified a viable hypomorphic allele (boh) of the transcription-factor-encoding gene Ovol2 that resulted in obesity, which initially developed with normal food intake and physical activity but decreased energy expenditure. Fat weight was dramatically increased, while lean weight was reduced in 12-week-old boh homozygous mice, culminating by 24 weeks in massive obesity, hepatosteatosis, insulin resistance, and diabetes. The Ovol2boh/boh genotype augmented obesity in Lepob/ob mice, and pair-feeding failed to normalize obesity in Ovol2boh/boh mice. OVOL2-deficient mice were extremely cold intolerant. OVOL2 is essential for brown/beige adipose tissue-mediated thermogenesis. In white adipose tissues, OVOL2 limited adipogenesis by blocking C/EBPα engagement of its transcriptional targets. Overexpression of OVOL2 in adipocytes of mice fed with a high-fat diet reduced total body and liver fat and improved insulin sensitivity. Our data reveal that OVOL2 plays dual functions in thermogenesis and adipogenesis to maintain energy balance.

FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance.

Fgf21 (fibroblast growth factor 21) is a regulatory hepatokine that, in pharmacologic form, powerfully promotes weight loss and glucose homeostasis. Although "Fgf21 resistance" is inferred from higher plasma Fgf21 levels in insulin-resistant mice and humans, diminished Fgf21 function is understood primarily via Fgf21 knockout mice. By contrast, we show that modestly reduced Fgf21-owing to cell-autonomous suppression by hepatic FoxO1-contributes to dysregulated metabolism in LDKO mice (Irs1L/L⋅Irs2L/L⋅CreAlb), a model of severe hepatic insulin resistance caused by deletion of hepatic Irs1 (insulin receptor substrate 1) and Irs2. Knockout of hepatic Foxo1 in LDKO mice or direct restoration of Fgf21 by adenoviral infection restored glucose utilization by BAT (brown adipose tissue) and skeletal muscle, normalized thermogenic gene expression in LDKO BAT, and corrected acute cold intolerance of LDKO mice. These studies highlight the Fgf21-dependent plasticity and importance of BAT function to metabolic health during hepatic insulin resistance.